Sage Journals: Discover world-class research

Abstract

Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of genetic mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains followed by backcrossing into more fecund mouse strains. Although common inbred mice are considered “immune competent,” many have variations in their immune system—some of which have been described—that may affect the phenotype. Recognition of these immune variations among commonly used inbred mouse strains is essential for the accurate interpretation of expected phenotypes or those that may arise unexpectedly. In GEM developed to study specific components of the immune system, accurate evaluation of immune responses must take into consideration not only the gene of interest but also how the background strain and microbial milieu contribute to the manifestation of findings in these mice. This article discusses points to consider regarding immunological differences between the common inbred laboratory mouse strains, particularly in their use as background strains in GEM.

Keywords

genetic engineering scid acquired immunity innate immunity pathogens immunodeficiency inbred mice immunophenotype phenotype GEM

Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains¹⁴¹ followed by backcrossing into the more fecund C57BL/6 strain or into other genetic backgrounds such as BALB/c and C3H to achieve specific experimental aims. The generation of “double mutant” mice may introduce additional genetic ambiguity into the resulting litters. Thus, the accurate interpretation of immune effects, whether expected or not, depends on one’s ability to recognize characteristics and variations among inbred mouse strains. In addition, the use of proper GEM nomenclature is important for appropriate comparisons between studies, since simple variations in background or target region have an impact on the phenotype. Appropriate nomenclature for GEM is described at http://www.informatics.jax.org/mgihome/nomen/index.shtml.

Immune responses are divided conceptually into innate and adaptive (acquired or cell-mediated) immunity. Innate immunity refers broadly to relatively immediate and nonspecific defenses, including (but not limited to) epithelial barriers, phagocytic cells (especially neutrophils and macrophages), natural killer cells, and complement activation. Deficiencies in innate immunity can be expected to affect both acute immune responses and the function and response of the adaptive immune system. Adaptive immunity is mediated by B and T lymphocytes, which have more specific targeting and longer term effects than innate immunity. However, the boundary between innate and adaptive immunity is not always distinct or mutually exclusive. For example, natural killer T (NKT) cells functionally bridge the innate and adaptive immune system, and there is increasing evidence of innate “memory,” recently termed trained immunity.¹¹⁸

Genetic manipulation of the immune system is of great value in understanding disease pathogenesis. Immune responses to pathogens are complex, as are autoimmune diseases, and genetic diversity contributes significantly to the susceptibility of the individual to disease. Dysregulation of the immune system that prevents normal responses to pathogens (an immune deficiency) may also promote defects in self-tolerance (autoimmunity) in that same animal.¹⁰⁹ In immunomodified GEM, the susceptibility to disease is defined not only by the targeted gene but also by the original genetic background (mouse strain) and the subsequent backcross strain; there are also environmental and epigenetic factors to consider. This review discusses selected examples of immunological variation between inbred mouse strains as they pertain to pathogen susceptibility, cellular injury response, and proclivity to autoimmune disease and how these variations may influence study outcomes in both wild-type mice and GEM.

The Innate Immune System

The initial innate response to pathogens is primarily mediated by pattern recognition receptors (PRRs). PRRs recognize non-self through conserved microbial structures termed pathogen-associated molecular patterns (PAMPs); damaged cells, in turn, are recognized through damage-associated molecular patterns (DAMPs). PRRs are present in both immune and nonimmune cells. In most cases, signaling through PRRs induces expression of proinflammatory cytokines, interleukins (ILs), chemokines, and antimicrobial proteins (eg, opsonins and defensins). PRRs fall into 4 families: (1) Toll-like receptors (TLRs); (2) C-type lectin receptors (CLRs); (3) retinoic acid–inducible gene-I-like receptors (RLRs); and (4) NOD-like receptors (NLRs).^65,155 Dysfunctional signaling of the PRR system may result in immunodeficiency and autoimmunity.^65,155

Of the PRRs, the TLRs are the most studied and best understood. TLRs often form heterodimers to recognize microbial PAMPs as well as endogenous molecules from damaged cells (DAMPs). A lack of TLR signaling results in notable immunodeficiency.⁸³ At present, there are 10 reported human TLRs and 13 mouse TLRs.¹³⁹ TLRs expressed on the cell membrane (TLRs 1, 2, 4, 5, 6, and 11) primarily detect viral, bacterial, fungal, and protozoal-associated proteins and structures, whereas 5 TLRs located intracellularly on endosomal membranes (TLRs 3, 7, 8, 9, and 13) detect nucleic acids (eg, ssRNA, ssDNA, CpG motifs, etc).^131,139 TLR10, although expressed in humans, is disrupted by retroviral sequences in most laboratory mice and is not expressed.⁵⁷ There are 5 adaptor proteins associated with the TLR receptors, of which myeloid differentiation primary-response gene 88 protein (MYD88) is common to all except TLR3, which instead uses TIR-domain–containing adapter-inducing interferon-β (TRIF).^15,171

In addition to their function in pathogen recognition, TLRs are important in recognizing cell damage. For example, TLR4 has been demonstrated to be an important factor in a number of non–pathogen-associated inflammatory diseases, including atherosclerosis and ischemia–reperfusion injury. Apoe mutant mice (which develop atherosclerosis) have reductions in the accumulation of foam cells if they are additionally deficient in Tlr4 or, to a lesser extent, deficient in Tlr2.¹⁴⁴ Tlr4 mutant and or Tlr2 mutant mice also have protection against injury in cardiac, liver, brain, and kidney ischemia in ischemia–reperfusion models.^2,67,168

The RLR family consists of RIG-I, melanoma differentiation-associated gene 5 (MDA5), and LGP2. These proteins are located in the cytoplasm and recognize dsRNA, either from dsRNA viruses or as the replication intermediate of ssRNA viruses.¹⁵⁵ As is the case with RLRs, NLRs act as cytoplasmic sensors of pathogens. Many NLRs are components of the so-called inflammasome and do not initiate transcription of proinflammatory cytokines. Inflammasomes are multiprotein complexes that are present in myeloid cells and activate caspase 1, although the precise composition of an inflammasome varies depending on initiating stimulus. The role of the inflammasome is to activate the innate inflammatory response and induce cell pyroptosis, a programmed cell death that is discrete from apoptosis.^87,142 Of the NLRs, NOD1 and NOD2 are associated with bacterial recognition, and NOD2 has recently been demonstrated to initiate inflammation in response to respiratory syncytial virus infection.¹³⁵ The CLRs are transmembrane receptors that recognize carbohydrates. Examples of CLRs are dectin-1, dectin-2, and the macrophage C-type lectin, MINCLE. Dectin-1 and -2 generally (but not exclusively) respond to fungi, whereas ⁴⁷ MINCLE responds to spliceosome-associated protein 130 (SAP130) from necrotic cells.¹⁸¹

The Adaptive Immune System

Adaptive immune responses are initiated by innate immune reactions so deficiencies in innate immunity translate to defective adaptive immunity. B and T lymphocytes and their sublineages are the effector cells of the adaptive immune system. Strains such as the SJL/J have inverted B- to T-cell ratios compared with C57BL/6. Thus, SJL/J mice have a notably lower percentage of circulating B lymphocytes versus T lymphocytes compared with C57BL/6 mice.^22,23,48 In T cells, antigen receptors (T-cell receptors, or TCRs) are expressed at the cell surface.¹³ T cells are divided into 2 TCR sublineages: (1) those expressing the αβ TCR, which are the most common type, and (2) those expressing the γδ TCR. γδT cells have features of both the innate and acquired immune system.^177,178 In contrast, B cells both secrete immunoglobulins and express them on their cell surface. B cells also have sublineages, termed B1 and B2. T and B cells are exposed to antigens by antigen presenting cells (APCs), such as dendritic cells, that secrete IL-1 to activate T cells (reviewed in references 85 and 86).

Functional antigen receptors (either immunoglobulins or TCRs) are generated by a genetic process whereby gene segments are spliced together by variable, diversity, and joining [V(D)J] recombination. The diversification of antigen receptor genes is further guided by the mechanisms of somatic hypermutation and class-switch recombination. V(D)J recombination uses the recombination activating genes 1 (RAG1) and RAG2 complexes to generate unique T-cell receptor sequences (eg, TCRα and TCRβ chains) and B-cell immunoglobulin heavy (IgH) and light (IgL) chains.¹³⁸

T cells can differentiate into several subtypes: T-helper cells (TH cells; CD4+), cytotoxic T cells (TC; CD8+), memory T cells (TCM or TEM; these may be CD4 or CD8+), regulatory T cells (Treg—formerly T suppressor cells; CD4+), natural killer T cells (NKT & CD8+NKT), and CD4FH T cells (follicular helper cells).^74,128 Differentiation of T cells into specific subsets depends on the cytokine milieu to which they are exposed. For example, differentiation into T-helper cells is mediated by interferon γ (IFNγ) combined with IL-12, IL-18 (for TH1 cells), IL-4 (for TH2 cells), IL-6, transforming growth factor β (TGFβ), IL-23 (for TH17 cells), and IL-21 (for THFH cells). Differentiation into Tregs is through the polarizing effects of IL-6 and TGFβ. Differentiation into cytotoxic CD8⁺ T-cells is mediated primarily by IL-2.^{11,20,52,55,123,172}

New research also highlights the role of microRNAs (miRNAs) in the immune system. MicroRNAs are small noncoding RNAs that regulate gene expression. It is believed that miRNAs exert regulatory control through inhibiting translation and regulating the stability of mRNAs.¹⁸ In the immune system, miRNAs are thought to play an important role in hematopoietic cell maturation, monocyte activation, B- and T-cell responses and homeostasis, and T-cell selection in the thymus.^21,72,91Alterations in miRNAs have been demonstrated to affect the immune responses to pathogens and self-antigens, and certain disruptions in miRNA expression have been associated with autoimmune diseases.^30,89,117 No specific data are present in the literature on the variation of miRNA expression in the immune system of the different inbred mouse strains; this would be an interesting area of future study that could improve our understanding of strain variations in the immune and other systems.

Immune Variation Among Inbred Mouse Strains: Selected Examples

Innate Immunity

Toll-Like Receptors

As previously described, TLRs mediate responses to pathogens and tissue damage; defects in TLR signaling may result in susceptibility to infection, abnormal tissue healing after ischemic injury, and autoimmune disease. TLR4 is the primary receptor for recognition of lipopolysaccharide (LPS) on gram-negative bacteria and the capsule of Cryptococcus neoformans—and also glycoinositophospholipids from Trypanosoma cruzi. ^124,140 As a general rule, Tlr4 mutant mice are more susceptible to gram-negative infections, such as Klebsiella pneumonia.¹⁷⁴Among the more common laboratory mouse strains, only C3H/HeJ has a point mutation in the Tlr4 gene that renders it unresponsive to LPS. A less common strain, C57BL10/ScCr, has a different null mutation of Tlr4.¹³⁰ However the C3H/HeJ-related strains—among them C3H/HeN and C3H/HeOuJ—have a functional TLR4 receptor and respond normally to LPS.^130,150 Increased susceptibility of C3H/HeJ mice to infections with several gram-negative bacteria has been attributed to the defect in the Tlr4 gene.^122,167,179 However, a recent study using Escherichia coli in a model of urinary tract infection suggest that the Tlr4 mutation is not the sole factor in the susceptibility of the C3H/HeJ mouse to infection, since C3H/HeOuJ female mice are also highly susceptible to bladder infection by E. coli.¹⁵⁰ Given these findings, additional factors (eg, from modifier genes) may prove to be relevant to the high susceptibility of these mice to gram-negative bacterial infections.

Complement Factor C5: Hemolytic Complement (Hc)

Hemolytic complement is also known as complement component 5 (C5). The role of the complement system is both to promote the elimination of pathogens and to mediate the removal of immune complexes, cellular debris, and apoptotic cells.^{24,63,107,112} The role of complement in immune-mediated diseases can be paradoxical. Activation of the complement system has been demonstrated to be important in the pathogenesis of autoimmune diseases.^60,63 However, deficiencies in the complement system that result in the accumulation of cellular components extracellularly and in the circulation may lead to an autoimmune response.^63,90

Several mouse strains including A/J, AKR/J, DBA/2, DBA/1, FVB/NJ, and SWR have a loss-of-function mutation in complement component 5 (C5) as a result of a frame shift in their Hc gene.¹⁷³ The mutation (Hc⁰ ) is implicated in altered pathogen susceptibility, although most variations in susceptibility are multifactorial and polygenic.¹⁷³ As a whole, strains with the Hc⁰ mutation are more susceptible to infection with Bacillus anthracis, Aspergillus fumigatus, and Candida albicans compared with the C57BL/6 strain, which has intact C5.^{56,114,132,152,163} However, strains with Hc⁰ are associated with lower susceptibility to cerebral malaria after infection with Plasmodium berghei, as a result of reduced C5a-induced cytokine expression.¹²⁶ C5 has also been shown to play a role in the development of immune-mediated diseases in mice. For example, DBA/1 mice (and in all likelihood, some of the strains listed above) are resistant to collagen-induced arthritis.¹⁶⁹ In C57BL/6NHsd mice, inhibition of complement factor C5 protects against anti-myeloperoxidase antibody–mediated glomerulonephritis in mice.⁶³ Consideration therefore must be given to the C5 status of a strain prior to the evaluation of disease—and similar scrutiny rendered when evaluating the genetic history of GEM in immunological studies.

NOD-Like Receptor-Nlrp (Nalp)

NLR proteins, as previously described, may incite inflammation or may act as sensor components in inflammasome complexes. NLR family pyrin domain–containing (Nlrp) gene family members play an important role in susceptibility and resistance to infections: polymorphisms within this class of NLRs have been associated with autoimmune diseases in humans.^1,66 In mice, a particular Nlrp1b polymorphism has been studied in relation to responses to the anthrax lethal toxin (LT): alleles Nlrp1r^r/r and Nlrp1b^s/s . Anthrax LT has been demonstrated to induce caspase-1 and macrophage lysis only in mice harboring the Nlrp1b^s/s polymorphism. The typical Hc⁰ mice (eg, A/J, DBA/2, SWR/J, FVB/NJ, described above) are all susceptible to anthrax LT. Interestingly, mice carrying Hc⁰ survive longer after LT injection if they also carry the sensitive Nlrp1b^s/s polymorphism.^110,119 Mice with normal C5 function but expressing the resistant Nlrp1r^r/r allele (eg, C57BL/6) have shorter survival after exposure than those expressing the Nlrp1b^s/s gene (eg, BALB/cJ, CBA/J, C3H/HeJ, etc).¹¹⁰ The relationship between C5 and Nlrp1b polymorphisms in susceptibility to LT again demonstrates the complexity of protein interactions in the immune system and highlights the importance of understanding the genetic background of mice during study initiation and interpretation.

Killer Cell Lectin-Like Receptors (Klra; also called Ly49)

NK cells are important in both antiviral and other immune responses and are the primary source of IFNγ during the acute immune response.¹⁰² The Klra family of genes encodes a collection of type II c-type lectin-like receptors termed killer cell lectin-like receptors (KLRAs, also known as Ly49s). These KLRAs are expressed on mouse NK, NKT, and various memory CD8+ cells and can either activate or suppress cell signaling upon recognizing major histocompatibility complex class I proteins.^16,31,36,102 Activating KLRA receptors contain a region for association with the signal-transducing protein DAP12.¹⁰²

Studies of the Klra family of genes demonstrate that KLRAs are highly divergent between in-bred mouse strains, although overlap is present.^95,96 For example, Klra15 (Ly49O) and Klra15 (Ly49P) are expressed in 129/J mice, and Klra12 (Ly49L) is expressed in CBA/J and C3H/He mice: none of these, however, are expressed in C57BL/6 mice.

In relation to C57BL/6 mice, 129 mice are relatively resistant to tumor induction and have a lower tumor incidence than their C57BL/6 counterparts, which may in part be a result of differences in NK cell antitumor activity.^100,143 Similarly, 129X1/SvJ mice have reduced rejection of bone marrow grafts compared with C57BL/6, which has been demonstrated to be due to abnormal DAP12 signaling in 129X1/SvJ mice,^79,93 indicating an important role of NK cell activity in graft rejection in mice. Variations in KLRAs can result in specific resistance or susceptibilities to pathogens in various strains. For example, C57BL/6 mice have a unique resistance to murine cytomegalovirus (via expression of Klra8). ^29,31,37,38 It is likely that activation signaling by NK cells plays a role in these differential immune responses between inbred lab strains. Understanding differences in Klra expression among mice strains is important when generating mutant mice for immunological research, particularly those where the role of NK cells may be consequential.

Neuronal Apoptosis Inhibitory Protein

Neuronal apoptosis inhibitory proteins (NAIPs) belong to the inhibitor of apoptosis (IAP) family of antiapoptotic proteins.⁵⁸ NAIPs have been described to have antiapoptotic effects and can inhibit caspases through baculovirus inhibitor of apoptosis repeat (BIR) domains.⁴³ Defects in IAPs, including NAIP expression, has been associated with autoimmune diseases in humans.^58,113 Studies also indicate that NAIP protein expression is important in macrophage responses to phagocytic signals and the response to pathogens.^43,80 C57BL/6 mice express Naip1, Naip2, and Naip6, each of which apparently recognizes specific bacterial ligands.⁸⁰ Both Naip5 expression and Naip2 expression in C57BL/6 have been shown to be important in inflammasome activation by Salmonella enterica ser. Typhimurium.⁸⁰ The Naip5 gene has also been identified as the Legionella pneumophila susceptibility allele (Lgn-s).^43,101 The majority of inbred mouse strains carry wild-type Naip5 allele and are resistant to infection with L. pneumophila. However, the mice of the A/J strain carry the Lgn1-s allele, they are susceptible to infection with L. pneumophila, and their macrophages express significantly lower NAIP proteins than do macrophages derived from C57BL/6 mice.¹⁸⁰ The A/J mouse strain has also been used for its increased susceptibility to autoimmune disease. Because of the relationship between IAP defects in humans and autoimmune diseases, it is tempting to speculate that the Naip5 abnormalities in this strain may contribute to its autoimmune susceptibility.^32,98

Cathepsin E (Ctse)

Cathepsin E is an endosomal proteinase, expressed in some epithelial and hematopoietic cells, which has a role in lysosomal function and intracellular trafficking.¹⁵⁹ In mice, cathepsin E is expressed in the gastric epithelium as well as lymphocytes, dendritic cells, erythrocytes, and certain subsets of macrophages.^9,28,182,185 Macrophages in mice with inactivating mutations in cathepsin E (Ctse) have impaired chemotaxis and cell adhesion.¹⁵⁸ Defects in Cathepsin E have been associated with the development of atopic dermatitis (AD) in humans, and mice with deletion of Cathepsin E develop skin lesions similar to human AD.¹⁵⁸

C57BL/6JOlaHsd are very deficient in cathepsin E function in hematopoietic cells compared with the normal levels in 129S2/SvHsd and BALB/c OlaHsd mice.¹⁵⁹ C57BL/6 mice have been noted to respond poorly to certain antigens, and their relative deficiencies in cathepsin E may contribute to these findings, although restriction in MCH class II isotypes as well as other factors is likely also important.¹⁵⁹ Immune responses involving this cathepsin may be expected to be blunted in mice backcrossed in the C57BL/6 versus those backcrossed to 129, BALB/c, and other mouse strains.

Mx1 and Mx2

Mx1 and Mx2 encode GTPases that are induced by IFNα, IFNβ, and IFNγ.⁵³ In mice, MX1 confers resistance to intranuclear viruses, including orthomyxoviruses such as highly pathogenic avian influenza A virus and Thogoto virus.^{53,127,129,145,148} MX2 imparts resistance to cytoplasmic viruses such as the rhabdovirus, vesicular stomatitis virus,⁶⁸ and bunyaviruses such as LaCrosse virus and Hantaan virus (a Hantavirus) in mice.^70,71 In most inbred laboratory strains, such as C57BL/6, BALB/c, and CBA/J, both the Mx1 and Mx2 genes (located on the distal end of mouse chromosome 16) have mutations or deletions, whereas the wild mice Mus musculus musculus and Mus spretus have intact Mx genes.¹⁴⁵ A single common genetic ancestor of these inbred strains likely contributed the defective distal end of chromosome 16 to their genomes.^68,69,70,145

Oas1b

The Oas1b gene encodes a 2′-5′ oligoadenylate synthetase that confers resistance to flaviviruses.⁵¹ Expression of Oas1b is induced by IFN, and the OAS1B protein activates latent ribonuclease L, which can degrade viral RNA and thwart replication.^25,51 As with the Mx1 and Mx2 genes, common inbred strains of mice are much more susceptible to experimental flaviviruses (with the exception of the PL/J mouse) compared with wild mice or wild-derived inbred mice.⁵¹ The susceptibility of inbred strains of mice to flaviviruses is attributed to a point mutation in the Oas1b gene that is thought to result in a premature stop codon and thus a truncated protein.

Candida Albicans Resistance Loci Carg3 and Carg4

Candida albicans resistance loci (Carg) in mice also act as modifiers in host responses to C. albicans. For example, DBA/2 and A/J, which both carry Hc ⁰ and thus lack C5, are highly susceptible to infection with C. albicans. However, AKR/J mice, which also carry Hc ⁰, are less susceptible to C. albicans. Their resistance has been mapped to 2 Carg loci, one on chromosome 11 (Carg4) and one on chromosome 8 (Carg3).^3,4,132 The genes have not yet been defined, although several candidates have been suggested.¹³²

D7Mit341 to D7Mit247

This region (D7Mit341 to D7Mit247) of roughly 8 centimorgans on mouse chromosome 7 has been reported to be the location of a survival trait against illness associated with Streptococcus pneumoniae. This region includes genes encoding for molecules associated with inflammation and innate immunity such as the platelet activating factor acetylhydrolase 1B-γ subunit gene (Pafah1b3), the tyrosine kinase-binding protein gene (Tyrobp), nuclear factor-κB inhibition gene (Ikbb), and the hematopoietic cell signal transducer gene (Hcst). ⁷³ It is likely that genes in this region also affect responses to other bacterial pathogens. Susceptibility to experimental pneumococcal infection is highly strain dependent; strains from least to most sensitive include BALB/c, DBA/2, C57BL/6, NIH, AKR, FVB/N, CSH/He, SJL, and CBA/Ca.^35,73 CBA/Ca mouse studies have shown that after exposure to S. pneumonia, these mice fail to fully activate NF-κB, p38, and ERK1/2 MAPK signaling pathways and their macrophages have impaired secretion of several inflammatory cytokines.¹³⁴ The relationship of this finding to the genetic susceptibility region of chromosome 7 remains unresolved. 129X1/Sv mice are notably more susceptible to pneumococcal pneumonia than are C57BL/6 mice. Reduced alveolar macrophage phagocytosis of the bacteria, and thus decreased bacterial clearance, in 129X1/Sv mice are implicated as primary contributors to their susceptibility.¹⁵¹ Because many GEM have been generated using 129 ES cells and because the degree of backcrossing to C57BL/6 is often unknown or limited, comparisons of microbial susceptibility between different GEM may lead to inaccurate conclusions due to strain-related variations in relevant immune genotypes.

Adaptive Immune System Mutations

Numerous genetic mutations in adaptive immune genes have been generated in mice to better understand their roles in the clearance of pathogens. The most common spontaneous disease reported in GEM with adaptive immune defects is chronic colitis, which in some cases has been demonstrated to be associated with Helicobacter spp such as H. hepaticus and H. bilis, although 9 enterohepatic Helicobacter species have been named.^44,45,170 As with the innate immune system, strain variation in the adaptive immune response has an important impact on the phenotype in chronic colitis.⁹⁴ In general, the severity of colitis-related characteristics is greatest on C3H/HeJBir or 129X1/Sv, intermediate on BALB/cJ or NOD/Lt, and least on C57BL/10 or C57BL/6J.⁵ For example, mice homozygous for Il2^tm1Hor on the C57BL/6J genetic background that survive beyond 3–4 weeks develop inflammatory bowel disease (IBD).^62,136 The same mutation in BALB/c mice results in death from hemolytic anemia in all mice between 3 and 5 weeks of age.¹³⁷ IL-10–deficient GEM offer another mouse colitis model with background strain relevant variability. IL-10, which has roles in both the acquired and the innate immune systems, is generally considered an anti-inflammatory cytokine.^175,176 IL-10 mutations in the C57BL/6J background have much milder typhlocolitis compared with the same mutation in C3H/HeJBir background.⁹⁴ IL-10 mutations on the BALB/c or NOD/Lt background lead to intermediate progressive disease but severe progressive disease in 129/SvEv mice.^5,94 The higher susceptibility of the C3H/HeJBir to colitis has been localized to genes located in a region between D3Mit348 and D3Mit254 (∼130 megabases)^6,12 but also may be affected by defects in Tlr4 in these mice.

Background strain effects on immune phenotype of nude and SCID mice can be expected to influence phenotype in immune GEM. On different backgrounds, the Prkdc^scid (scid) mutation manifests varying severity of immune deficiency. Mice with serum immunoglobulin concentrations of 1 μg/mL or more are considered “leaky” (but may vary with vendor). C57BL/6J and BALB/cBy have a higher incidence of leakiness than C3H/HeJ with NOD/LtSz background.¹²¹ The degree of leakiness also increases with age and is greater in mice housed in conventional rooms. However, the functional consequences of leakiness are not well established, and it is not clear whether leaky mice respond differently than mice with undetectable immunoglobulin.

TH1 vs TH2 responses

Classically, TH1 cells are important in the clearance of intracellular pathogens, whereas TH2 cells are commonly associated with responses to parasitic infections. Segregation into TH1 or TH2 helper T cells is dependent primarily on the cytokines released by antigen presenting cells (APCs) that respond to pathogens via PRRs.^52,55,149 Many GEM are backcrossed into a C57BL/6 genetic background. C57BL/6 mice have been demonstrated to have a TH1-type bias to pathogens, whereas mice of other backgrounds, such as BALB/c, A/J, and DBA/2 mice, tend toward a TH2-predominant response.¹⁰⁸ These differences may also be reflected in the M-1 and M-2 macrophage responses to antigen stimulation. M-1 macrophages produce more nitric oxide (via inducible nitric oxide synthase) than do M-2 macrophages when exposed to IFN or LPS. M-1 macrophages are generally active in TH1 responders, and M-2 tend to be more active in TH2 responders.⁹⁷

TH1 or TH2 bias alone can be expected to affect outcomes in studies of pathogen susceptibility, particularly with intracellular organisms and parasites. For example, C57BL/6 and 129/SvEv mice are relatively resistant to infection with Leishmania major compared with BALB/c mice that are unable to control infection with this organism.¹⁵³ This is at least in part related to the TH2 cell dominance in BALB/c mice, as mice deficient in IL-12 (which drives a TH1 response) are highly susceptible to L. major. ⁹⁹ Although IL-12 treatment in BALB/c mice does reduce susceptibility to L. major, ¹⁵⁴ theoretically through promoting a TH1 type response, GEM that express no IL- 4 (which normally drives a TH2 response) are as susceptible to L. major, similar to BALB/c.¹²⁰ Likewise, clearance of other intracellular organisms such as Francisella tularensis, T. cruzi, Encephalitozoon cuniculi, and Toxoplasma gondii is dependent on IFNγ-induced IL-12 expression, which promotes a TH1 response.^{39,84,111,180} C57BL/6 mice, with relatively TH1-biased responses, are generally more resistant to these organisms than other strains of mice.

T-Cell Receptor β, Variable 8 (Tcrb-V8)

SJL/J, FVB/NJ, SWR, C57L, and C57BR strains have germline deletions in the Tcrb-V8 gene, with SJL/J mice having the largest amount of DNA deleted.^7,8,125 TCRB-V8 is expressed on many cell types, including natural killer T (NKT) cells and CD8+NKT cells.⁴⁰ NKT cells coexpress TCRB-V8 and the natural killer (NK) cell marker NK1.1 and thus represent a hybrid of the innate and adaptive immune system. NKT cells also coexpress the semi-invariant CD1d-restricted αβ TCR. Although these cells are less than 1% of the T-cell population, they recognize a wide assortment of glycolipids in the context of CD1d presentation¹⁵⁶ and directly and indirectly respond to infectious agents.^133,160 Upon activation, NKT cells rapidly produce IFNγ and IL-4 as well as other cytokines such as IL-2, TNFα, and granulocyte-macrophage colony-stimulating factor (GMCSF).^77,183 Defects in NKT cell function have been associated with autoimmune diseases and microbial susceptibility, reduced cell-mediated anti-tumor activity, and NKT cells may have a role in the progression of asthma.^{26,27,46,49,50,64,82,88,115} In addition, TCRB-V8 has been demonstrated to serve as a receptor for exogenous MMTV, and defects in this receptor may promote immunity to lentivirus infections.¹⁶¹ For further discussions on the unique immune profile of SJL mice, see reference 48.

Signaling lymphocyte activation molecule family (Slamf)

The signaling lymphocyte activation molecule family (Slamf) consists of cell surface receptors expressed on immune cells that play an important regulatory role in both the innate and adaptive immune system.^{10,17,78,81,166} SLAMF receptors are expressed on myeloid cells, and studies have shown that they play an important role in bacterial killing through regulating enzyme activity in the phagosome of macrophages.¹⁰ Polymorphisms in the Slamf genes are also associated with lupus-like syndromes in both the human and mouse. Slamf1 and Slamf2 have been demonstrated to be important in mediating self-tolerance in mice and lie within the lupus-associated Sle1b region.^17,81,166 Deletion of Slamf2 (CD48) in 129 ES cells followed by crossing into C57BL6 to generate 129.B6 resulted in mice that develop a lupus-like syndrome. However, mice crossed into a BALB/c genetic background (BALB.129) did not develop autoimmune disease.^78,81

Solute Carrier Family 11a Member 1 Slc11a1 (Nramp1, Ity, Lsh, and Bcg)

Solute carrier family 11a member 1 (Slc11a1) encodes the protein formerly known as murine natural resistance–associated macrophage protein 1. The gene encodes a metal ion transporting protein and localizes to phagolysosomes in neutrophils and monocytic phagocytic cells.^43,147 It is theorized that the gene product attenuates intracellular pathogen replication in phagolysosomes by exporting metals needed for these processes.⁴³ SLC11A1 promotes a TH1 type of response, favoring IL-12 release by activated macrophages and dendritic cells.¹⁴⁷ The gene (locus) was also known as Ity, Lsh, and Bcg because of its role in controlling innate resistance and susceptibility to Salmonella typhimurium, Leishmania donovani, and Mycobacterium spp.^{14,103

–106,164,165} C57BL/6J and BALB/c mice carry the s (susceptibility) mutation in the Slc11a1 gene, which truncates the protein and increases susceptibility to infection with Mycobacteria spp and Salmonella spp. Strains129X1/Sv and C3H/HeN carry the r (resistance) allele, which confers resistance to these organisms.^19,43,162 Thus differing Slc11a1 genotypes may also contribute to varying immune responses in GEM derived from 129 ES cells and incompletely backcrossed into C57BL/6.

Major Histocompatibility Complex (MHC) Molecules

The MHC molecules are present on the surface of all nucleated cell types. MHC molecules are divided into 3 classes: MHC class I and MHC class II genes, which encode for antigen-presenting MHC molecules,⁶¹ and MHC class III molecules, which have immune and nonimmune functions.¹⁸⁴ The MHC molecules are designated as H-2, for histocompatibility: H-2 class I and H-2 class II molecules. The MHC H-2 complexes have been separated into MHC class I or MHC class II alloantigens⁴² ^33,34,75 Each mouse strain has its own MHC haplotypes for each of these alloantigens, which are designated by a small letter. Often strains are identified by a single MHC haplotype: H2^d in BALB/c and NZB/B1NJ mice and H2 ^k in C3H/HeJ and B10.BR strains, despite the fact that they may differ at some of the other MHC alloantigens.^41,92 The H-2 haplotype is important to consider in transplantation studies (eg, graft-vs-host reactions) as well as in the susceptibility and response to pathogens. For example, the susceptibility to chronic disease following infection with respiratory syncytial virus (RSV) infection is in part MHC dependent.¹⁵⁷ Immune responses to RSV are variable between inbred mouse strains. C3H/HeN (H-2 ^k) mice are relatively resistant to RSV, whereas BALB/c (H-2^b) mice are relatively sensitive to infection.^146,157 Strain haplotype also appears to be important in susceptibility to autoimmune diseases. Mouse strains with H-2^d and H-2 ^k haplotypes tend to have less severe lupus nephritis relative to H2^b and H2^bm12 when crossed with mice prone to lupus (eg, Fas^lpr mice,⁷⁶ BXSB mice,⁵⁹ and Nzb.H-2^bm12 mice^54,116).

Conclusions

Immune variations between the common inbred laboratory mouse strains are notable and affect responses to pathogens and cell damage as well as susceptibility to autoimmune diseases. Understanding and using these differences improve our understanding of immune reactions. Unfortunately, the genetic history of GEM is often ambiguous or not available. This is in large part due to GEM sharing between institutions and the development of “subcolonies” at those institutions. Because of the high cost of in vivo studies and the paucity of funding, investigators may choose to breed only mutant mice as well as interbreed different mutant mice, resulting in the loss of true controls. Study interpretation may thus be hampered by the use of inappropriate “wild-type” controls. It is quite common for investigators to simply use wild-type mice purchased from an outside vendor as the control. Unfortunately, the genetic background, microbiota, and environmental history of such a wild-type mouse may greatly diverge from the lines of in-house mutant mice, attenuating its value as a control mouse. Therefore, it is essential to gather as much genetic history as possible for mice under evaluation. Armed with that knowledge, the pathologist may then endeavor to review any pertinent literature, such as that reviewed here, regarding potential relevant modifier genes that could affect the study conclusions. Ultimately, immunological variation is the norm and not the exception, and the researcher and pathologist alike must view immunological findings from this perspective.

Footnotes

Acknowledgements

We give many thanks to John Englert for his editorial comments and suggestions.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Agostini

Martinon

Burns

. NALP3 forms an IL-1beta-processing inflammasome with increased activity in muckle-wells autoinflammatory disorder. Immunity. 2004;20:319–325.

Arslan

Keogh

McGuirk

. TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm. 2010;2010:704202.

Ashman

. Candida albicans: pathogenesis, immunity and host defense. Res Immunol. 1998;149:281–288; discussion 494-286.

Ashman

. A gene (Carg1) that regulates tissue resistance to Candida albicans maps to chromosome 14 of the mouse. Microb Pathog. 1998;25:333–335.

Bahring

Milligan

Vardanyan

. Coupling of voltage-dependent potassium channel inactivation and oxidoreductase active site of Kvbeta subunits. J Biol Chem. 2001;276:22923–22929.

Beckwith

Cong

Sundberg

. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology. 2005;129:1473–1484.

Behlke

Chou

Huppi

. Murine T-cell receptor mutants with deletions of beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986;83:767–771.

Behlke

Loh

. Alternative splicing of murine T-cell receptor beta-chain transcripts. Nature. 1986;322:379–382.

Bennett

Levine

Ellis

. Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E. Eur J Immunol. 1992;22:1519–1524.

10.

Berger

Romero

. SLAM is a microbial sensor that regulates bacterial phagosome functions in macrophages. Nat Immunol. 2010;11:920–927.

11.

Bettelli

Carrier

Gao

. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–238.

12.

Bleich

Büchler

Beckwith

. Cdcs1 a major colitis susceptibility locus in mice; Subcongenic analysis reveals genetic complexity. Inflamm Bowel Dis. 2010;16:765–775.

13.

Boehm

. Design principles of adaptive immune systems. Nat Rev Immunol. 2011;11:307–317.

14.

Bradley

. Letter: Genetic control of natural resistance to Leishmania donovani. Nature. 1974;250:353–354.

15.

Brown

Wang

Hajishengallis

. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 2011;90:417–427.

16.

Brown

Dokun

Heusel

. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science. 2001;292:934–937.

17.

Calpe

Wang

Romero

. The SLAM and SAP gene families control innate and adaptive immune responses. Adv Immunol. 2008;97:177–250.

18.

Carissimi

Fulci

Macino

. MicroRNAs: Novel regulators of immunity. Autoimmun Rev. 2009;8:520–524.

19.

Caron

Loredo-Osti

Laroche

. Identification of genetic loci controlling bacterial clearance in experimental Salmonella enteritidis infection: an unexpected role of Nramp1 (Slc11a1) in the persistence of infection in mice. Genes Immun. 2002;3:196–204.

20.

Carrier

Yuan

Kuchroo

. Th3 cells in peripheral tolerance, I: induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol. 2007;178:179–185.

21.

Chen

Lodish

. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–86.

22.

Chen

Flurkey

Harrison

. A reduced peripheral blood CD4(+) lymphocyte proportion is a consistent ageing phenotype. Mech Ageing Dev. 2002;123:145–153.

23.

Chen

Harrison

. Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood. Blood. 2002;99:561–566.

24.

Chen

Daha

Kallenberg

CGM

. The complement system in systemic autoimmune disease. J Autoimmun. 2009;34: J276–J286.

25.

Clemens

Vaquero

. Inhibition of protein synthesis by double-stranded RNA in reticulocyte lysates: evidence for activation of an endoribonuclease. Biochem Biophys Res Commun. 1978;83:59–68.

26.

Cohen

Garg

Brenner

. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv Immunol. 2009;102:1–94.

27.

Cohen

Garg

Brenner

. Antigen presentation by CD1: lipids, T cells, and NKT cells in microbial immunity. Adv Immunol. 2009;102:1–94.

28.

Cook

Caswell

Richards

. Regulation of human and mouse procathepsin E gene expression. Eur J Biochem. 2001;268:2658–2668.

29.

Corbett

Coudert

Forbes

. Functional consequences of natural sequence variation of murine cytomegalovirus m157 for ly49 receptor specificity and NK cell activation. J Immunol. 2011;186:1713–1722.

30.

Dai

Huang

Tang

. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus. 2007;16:939–946.

31.

Daniels

Devora

Lai

. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J Exp Med. 2001;194:29–44.

32.

del Rio

Sun

Alard

. H2 control of natural T regulatory cell frequency in the lymph node correlates with susceptibility to day 3 thymectomy-induced autoimmune disease. J Immunol. 2011;186:382–389.

33.

Demant

Ivanyi

Oudshoorn-Snoek

. Genetic complexity of H-2 antigens. Transplant Proc. 1981;13:1755–1758.

34.

Demant

Ivanyi

Oudshoorn-Snoek

. Molecular heterogeneity of H-2 antigens. Immunol Rev. 1981;60:5–22.

35.

Denny

Hopes

Gingles

. A major locus conferring susceptibility to infection by Streptococcus pneumoniae in mice. Mamm Genome. 2003;14:448–453.

36.

Desrosiers

Kielczewska

Loredo-Osti

. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection. Nat Genet. 2005;37:593–599.

37.

Dokun

Chu

Yang

. Analysis of in situ NK cell responses during viral infection. J Immunol. 2001;167:5286–5293.

38.

Dokun

Kim

Smith

. Specific and nonspecific NK cell activation during virus infection. Nat Immunol. 2001;2:951–956.

39.

Elkins

Cooper

Colombini

. In vivo clearance of an intracellular bacterium, Francisella tularensis LVS, is dependent on the p40 subunit of interleukin-12 (IL-12) but not on IL-12 p70. Infect Immun. 2002;70:1936–1948.

40.

Emoto

Zerrahn

Miyamoto

. Phenotypic characterization of CD8+NKT cells. Eur. J. Immunol. 2000;30:2300–2311.

41.

Fischer Lindahl

. On naming H2 haplotypes: functional significance of MHC class Ib alleles. Immunogenetics. 1997;46:53–62.

42.

Forman

Lindahl

. Listing, location, binding motifs, and expression of nonclassical class I and related genes and molecules. Curr Protoc Immunol. 2002 Aug; Appendix 1: Appendix 1M.

43.

Fortier

Min-Oo

Forbes

. Single gene effects in mouse models of host: pathogen interactions. J Leukocyte Biol. 2005;77:868–877.

44.

Fox

Whary

. Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer. Mucosal Immunol. 2011;4:22–30.

45.

Fox

Yan

Shames

. Persistent hepatitis and enterocolitis in germfree mice infected with Helicobacter hepaticus. Infect Immun. 1996;64:3673–3681.

46.

Garg

Sharma

Ung

. Lysosomal trafficking, antigen presentation, and microbial killing are controlled by the Arf-like GTPase Arl8b. Immunity. 2011;35:182–193.

47.

Geijtenbeek

Gringhuis

. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol. 2009;9:465–479.

48.

Glineur

Antoine-Moussiaux

Michaux

. Immune depression of the SJL/J mouse, a radioresistant and immunologically atypical inbred strain. Immunobiology. 2011;216:213–217.

49.

Gombert

Herbelin

Tancrede-Bohin

. Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. Eur J Immunol. 1996;26:2989–2998.

50.

Gombert

Herbelin

Tancrede-Bohin

. Early defect of immunoregulatory T cells in autoimmune diabetes. C R Acad Sci III. 1996;319:125–129.

51.

Guenet

. Assessing the genetic component of the susceptibility of mice to viral infections. Brief Funct Genomic Proteomic. 2005;4:225–240.

52.

Gutcher

Becher

. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007;117:1119–1127.

53.

Haller

Stertz

Kochs

. The Mx GTPase family of interferon-induced antiviral proteins. Microbes Infect. 2007;9:1636–1643.

54.

Hannestad

Scott

. The MHC haplotype H2b converts two pure nonlupus mouse strains to producers of antinuclear antibodies. J Immunol. 2009;183:3542–3550.

55.

Harrington

Hatton

Mangan

. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–1132.

56.

Harvill

Lee

Grippe

. Complement depletion renders C57BL/6 mice sensitive to the bacillus anthracis sterne strain. Infect Immun. 2005;73:4420–4422.

57.

Hasan

Chaffois

Gaillard

. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol. 2005;174:2942–2950.

58.

Hebb

Moore

Bhan

. Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination. Mult Scler. 2008;14:577–594.

59.

Hogarth

Slingsby

Allen

. Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. J Immunol. 1998;161:2753–2761.

60.

Holers

Thurman

. The alternative pathway of complement in disease: opportunities for therapeutic targeting. Mol Immunol. 2004;41:147–152.

61.

Holling

Schooten

van Den Elsen

. Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men. Hum Immunol. 2004;65:282–290.

62.

Horak

Lohler

. Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev. 1995;148:35–44.

63.

Huugen

van Esch

Xiao

. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int. 2007;71:646–654.

64.

Iwamura

Nakayama

. Role of NKT cells in allergic asthma. Curr Opin Immunol. 2010;22:807–813.

65.

Jeannin

Jaillon

Delneste

. Pattern recognition receptors in the immune response against dying cells. Curr Opin Immunol. 2008;20:530–537.

66.

Jeru

Duquesnoy

Fernandes-Alnemri

. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008;105:1614–1619.

67.

Jiang

Tang

Geng

. Inhibition of Toll-like receptor 4 with vasoactive intestinal peptide attenuates liver ischemia-reperfusion injury. Transplant Proc. 2011;43:1462–1467.

68.

Jin

Takada

Kon

. Identification of the murine Mx2 gene: interferon-induced expression of the Mx2 protein from the feral mouse gene confers resistance to vesicular stomatitis virus. J Virol. 1999;73:4925–4930.

69.

Jin

Yamashita

Ochiai

. Characterization and expression of the Mx1 gene in wild mouse species. Biochem Genet. 1998;36:311–322.

70.

Jin

Yoshimatsu

Takada

. Mouse Mx2 protein inhibits hantavirus but not influenza virus replication. Arch Virol. 2001;146:41–49.

71.

Jin

Y-H

Kang

Mohindru

. Preferential induction of protective T cell responses to Theiler's virus in resistant (C57BL/6 x SJL)F1 Mmice. J Virol. 2011;85:3033–3040.

72.

Johnnidis

Harris

Wheeler

. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125–1129.

73.

Kadioglu

Andrew

. Susceptibility and resistance to pneumococcal disease in mice. Brief Funct Genomic Proteomic. 2005;4:241–247.

74.

Karamitros

Kotantaki

Lygerou

. T cell proliferation and homeostasis: an emerging role for the cell cycle inhibitor geminin. Crit Rev Immunol. 2011;31:209–231.

75.

Kaufman

Auffray

Korman

. The class II molecules of the human and murine major histocompatibility complex. Cell. 1984;36:1–13.

76.

Kelley

Roths

. Interaction of mutant lpr gene with background strain influences renal disease. Clin Immunol Immunopathol. 1985;37:220–229.

77.

Kennedy

Vicari

Saylor

. A molecular analysis of NKT cells: identification of a class-I restricted T cell-associated molecule (CRTAM). J. Leukocyte Biol. 2000;67:725–734.

78.

Keszei

Latchman

Vanguri

. Auto-antibody production and glomerulonephritis in congenic Slamf1–/– and Slamf2–/– [B6.129] but not in Slamf1–/– and Slamf2–/– [BALB/c.129] mice. Int Immunol. 2011;23:149–158.

79.

Kielczewska

Kim

Lanier

. Critical residues at the Ly49 natural killer receptor's homodimer interface determine functional recognition of m157, a mouse cytomegalovirus MHC class I-like protein. J Immunol. 2007;178:369–377.

80.

Kofoed

Vance

. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature. 2011;477:592–595.

81.

Koh

Njoroge

Feliu

. The SLAM family member CD48 (Slamf2) protects lupus-prone mice from autoimmune nephritis. J Autoimmun. 2011;37:48–57.

82.

Kojo

Adachi

Keino

. Dysfunction of T cell receptor AV24AJ18+, BV11+ double-negative regulatory natural killer T cells in autoimmune diseases. Arthritis Rheum. 2001;44:1127–1138.

83.

Yang

Bustamante

. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev. 2005;203:10–20.

84.

Kumar

Tarleton

. Antigen-specific Th1 but not Th2 cells provide protection from lethal Trypanosoma cruzi infection in mice. J Immunol. 2001;166:4596–4603.

85.

Kushwah

. Complexity of dendritic cell subsets and their function in the host immune system. Immunology. 2011;133:409–419.

86.

Kushwah

. Role of dendritic cells in the induction of regulatory T cells. Cell Biosci. 2011;1:20.

87.

Lamkanfi

Dixit

. Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol. 2011;187:597–602.

88.

Lee

H-H

Meyer

Goya

. Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity. J Immunol. 2010;185:5225–5235.

89.

Leng

R-X

Pan

H-F

Qin

W-Z

. Role of microRNA-155 in autoimmunity. Cytokine Growth Factor Rev. 2011;22:141–147.

90.

Lewis

Botto

. Complement deficiencies in humans and animals: links to autoimmunity. Autoimmunity. 2006;39:367–378.

91.

Chau

, Ebert PJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell. 2007;129:147–161.

92.

Lindahl

Byers

Dabhi

. H2-M3, a full-service class Ib histocompatibility antigen. Annu Rev Immunol. 1997;15:851–879.

93.

Lotzova

Savary

. Possible involvement of natural killer cells in bone marrow graft rejection. Biomedicine. 1977;27:341–344.

94.

Mahler

Leiter

. Genetic and environmental context determines the course of colitis developing in IL-10-deficient mice. Inflamm Bowel Dis. 2002;8:347–355.

95.

Makrigiannis

Anderson

. The murine Ly49 family: form and function. Arch Immunol Ther Exp (Warsz). 2001;49:47–50.

96.

Makrigiannis

Pau

Saleh

. Class I MHC-binding characteristics of the 129/J Ly49 repertoire. J Immunol. 2001;166:5034–5043.

97.

Martinez

. Regulators of macrophage activation. Eur J Immunol. 41:1531–1534.

98.

Massilamany

Gangaplara

Chapman

. Detection of cardiac myosin heavy chain-alpha-specific CD4 cells by using MHC class II/IAk tetramers in A/J mice. J. Immunol. Methods. 2011;372:107–118.

99.

Mattner

Magram

Ferrante

. Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response. Eur J Immunol. 1996;26:1553–1559.

100.

Mayer

Lilly

Duran-Reynals

. Genetically dominant resistance in mice to 3-methylcholanthrene-induced lymphoma. Proc Natl Acad Sci U S A. 1980;77:2960–2963.

101.

McDade

Shepard

Fraser

. Legionnaires' disease. N Engl J Med. 1977;297:1197–1203.

102.

McVicar

Winkler-Pickett

Taylor

. Aberrant DAP12 signaling in the 129 strain of mice: implications for the analysis of gene-targeted mice. J Immunol. 2002;169:1721–1728.

103.

Medina

North

. Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis. J Exp Med. 1996;183:1045–1051.

104.

Medina

North

. Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette-Guerin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity. Clin Exp Immunol. 1996;104:44–47.

105.

Medina

North

. Genetically susceptible mice remain proportionally more susceptible to tuberculosis after vaccination. Immunology. 1999;96:16–21.

106.

Medina

Rogerson

North

. The Nramp1 antimicrobial resistance gene segregates independently of resistance to virulent Mycobacterium tuberculosis. Immunology. 1996;88:479–481.

107.

Mevorach

Mascarenhas

Gershov

. Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med. 1998;188:2313–2320.

108.

Mills

Kincaid

Alt

. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164:6166–6173.

109.

Milner

Fasth

Etzioni

. Autoimmunity in severe combined immunodeficiency (SCID): lessons from patients and experimental models. J Clin Immunol. 2008;28:29–33.

110.

Moayeri

Crown

Newman

. Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment. PLoS Pathog. 2010;6: e1001222.

111.

Moretto

Lawlor

Khan

. Lack of interleukin-12 in p40-deficient mice leads to poor CD8+ T-cell immunity against Encephalitozoon cuniculi infection. Infect Immun. 2010;78:2505–2511.

112.

Morgan

Marchbank

Longhi

. Complement: central to innate immunity and bridging to adaptive responses. Immunology Letters. 2005;97:171–179.

113.

Mullauer

Gruber

Sebinger

. Mutations in apoptosis genes: a pathogenetic factor for human disease. Mutat Res Rev Mut Res. 2001;488:211–231.

114.

Mullick

Elias

Picard

. Dysregulated inflammatory response to Candida albicans in a C5-deficient mouse strain. Infect Immun. 2004;72:5868–5876.

115.

Murata

Kita

Sakamoto

. Limited TCR repertoire of infiltrating T cells in the kidneys of Sjogren's syndrome patients with interstitial nephritis. J Immunol. 1995;155:4084–4089.

116.

Naiki

Yoshida

Ansari

. Activation of autoreactive T-cell clones from NZB.H-2bm12 mice. J Autoimmun. 1994;7:275–290.

117.

Nakasa

Miyaki

Okubo

. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 2008;58:1284–1292.

118.

Netea Mihai

Quintin

Van

der

Meer Jos

. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9:355–361.

119.

Newman

Crown

Leppla

. Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages. Biochem Biophys Res Commun. 2010;398:785–789.

120.

Noben-Trauth

Kropf

Muller

. Susceptibility to Leishmania major infection in interleukin-4-deficient mice. Science. 1996;271:987–990.

121.

Nonoyama

Smith

Bernstein

. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol. 1993;150:3817–3824.

122.

O'Brien

Rosenstreich

Scher

. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J Immunol. 1980;124:20–24.

123.

O'Shea

Paul

. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 327:1098–1102.

124.

Oliveira

A-C

de Alencar

Tzelepis

. Impaired innate immunity in Tlr4–/– mice but preserved CD8+ T cell responses against trypanosoma cruzi in Tlr4-, Tlr2-, Tlr9- or Myd88-deficient mice. PLoS Pathog. 2010;6: e1000870.

125.

Osman

Hannibal

Anderson

. T-cell receptor vbeta deletion and valpha polymorphism are responsible for the resistance of SWR mouse to arthritis induction. Immunogenetics. 1999;49:764–772.

126.

Patel

Berghout

Lovegrove

. C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J Exp Med. 2008;205:1133–1143.

127.

Pavlovic

Schroder

Blank

. Mx proteins: GTPases involved in the interferon-induced antiviral state. Ciba Found Symp. 1993;176:233–243; discussion 243-237.

128.

Pepper

Jenkins

. Origins of CD4(+) effector and central memory T cells. Nat Immunol. 2011;12:467–471.

129.

Pitossi

Blank

Schroder

. A functional GTP-binding motif is necessary for antiviral activity of Mx proteins. J Virol. 1993;67:6726–6732.

130.

Poltorak

Smirnova

. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–2088.

131.

Prince

Whyte

Sabroe

. The role of TLRs in neutrophil activation. Curr Opin Pharm. 2011;11:397–403.

132.

Radovanovic

Mullick

Gros

. Genetic control of susceptibility to infection with Candida albicans in mice. PLoS One. 2011;6: e18957.

133.

Ragin

Sahu

August

. Differential regulation of cytokine production by CD1d-restricted NKT cells in response to superantigen staphylococcal enterotoxin B exposure. Infect Immun. 2006;74:282–288.

134.

Ripoll

Kadioglu

Cox

. Macrophages from BALB/c and CBA/Ca mice differ in their cellular responses to Streptococcus pneumoniae. J. Leukocyte Biol. 2010;87:735–741.

135.

Sabbah

Chang

Harnack

. Activation of innate immune antiviral responses by Nod2. Nat Immunol. 2009;10:1073–1080.

136.

Sadlack

Lohler

Schorle

. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol. 1995;25:3053–3059.

137.

Sadlack

Löhler

Schorle

. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur J Immunol. 1995;25:3053–3059.

138.

Schatz

. Recombination centres and the orchestration of V(D)J recombination. Nat Rev Immunol. 2011;11:251–263.

139.

Shi

Cai

Sanchez

. A novel toll-like receptor that recognizes vesicular stomatitis virus. J Biol Chem. 2011;286:4517–4524.

140.

Shoham

Huang

Chen

. Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol. 2001;166:4620–4626.

141.

Simpson

Linder

Sargent

. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet. 1997;16:19–27.

142.

Skeldon

Saleh

. The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections. Front Microbiol. 2011;2:15.

143.

Smith

Walford

Mickey

. Lifespan and incidence of cancer and other diseases in selected long-lived inbred mice and their F 1 hybrids. J Natl Cancer Inst. 1973;50:1195–1213.

144.

Sorrentino

Arditi

. Innate immunity, Toll-like receptors, and atherosclerosis: mouse models and methods. Methods Mol Biol. 2009;517:381–399.

145.

Staeheli

Pitossi

Pavlovic

. Mx proteins: GTPases with antiviral activity. Trends Cell Biol. 1993;3:268–272.

146.

Stark

McDowell

Koenigsknecht

. Genetic susceptibility to respiratory syncytial virus infection in inbred mice. J Med Virol. 2002;67:92–100.

147.

Stober

Brode

White

. Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function. Infect Immun. 2007;75:5059–5067.

148.

Stranden

Staeheli

Pavlovic

. Function of the mouse Mx1 protein is inhibited by overexpression of the PB2 protein of influenza virus. Virology. 1993;197:642–651.

149.

Strutt

McKinstry

Swain

. Functionally diverse subsets in CD4 T cell responses against influenza. J Clin Immunol. 2009;29:145–150.

150.

Suhs

Marthaler

, Welch RA, et al. Lack of association between the Tlr4 (Lpsd/Lpsd) genotype and increased susceptibility to Escherichia coli bladder infections in female C3H/HeJ mice. mBio. 2011;2: e00094–11.

151.

Sun

Gan

Metzger

. Analysis of murine genetic predisposition to pneumococcal infection reveals a critical role of alveolar macrophages in maintaining the sterility of the lower respiratory tract. Infect Immun. 2011;79:1842–1847.

152.

Svirshchevskaya

Shevchenko

Huet

. Susceptibility of mice to invasive aspergillosis correlates with delayed cell influx into the lungs. Int J Immunogenet. 2009;36:289–299.

153.

Swihart

Fruth

Messmer

. Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response. J Exp Med. 1995;181:961–971.

154.

Sypek

Chung

Mayor

. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993;177:1797–1802.

155.

Takeuchi

Akira

. Pattern recognition receptors and inflammation. Cell. 2010;140:805–820.

156.

Tefit

Davies

Serra

. NKT cell responses to glycolipid activation. Methods Mol Biol. 2010;626:149–167.

157.

Tregoning

Yamaguchi

Wang

. Genetic susceptibility to the delayed sequelae of neonatal respiratory syncytial virus infection is MHC dependent. J Immunol. 2010;185:5384–5391.

158.

Tsukuba

Yanagawa

Okamoto

. Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages. J Biol Chem. 2009;145:565–573.

159.

Tulone

Tsang

Prokopowicz

. Natural cathepsin E deficiency in the immune system of C57BL/6J mice. Immunogenetics. 2007;59:927–935.

160.

Tupin

Kinjo

Kronenberg

. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Micro. 2007;5:405–417.

161.

Upragarin

Nishimura

Wajjwalku

. T cells bearing Vbeta8 are preferentially infected with exogenous mouse mammary tumor virus. J Immunol. 1997;159:2189–2195.

162.

Valdez

Grassl

Guttman

. Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice. Cell Microbiol. 2009;11:351–362.

163.

Veazey

Horohov

Krahenbuhl

. Comparison of the resistance of C57BL/6 and C3H/He mice to infection with Mycobacterium paratuberculosis. Veterinary Microbiology. 1995;47:79–87.

164.

Vidal

Tremblay

Govoni

. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med. 1995;182:655–666.

165.

Vidal

Malo

Vogan

. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell. 1993;73:469–485.

166.

Wandstrat

Nguyen

Limaye

. Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity. 2004;21:769–780.

167.

Wang

Moser

Louboutin

. Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. J Immunol. 2002;168:810–815.

168.

Wang

Abarbanell

Herrmann

. Toll-like receptor signaling pathways and the evidence linking toll-like receptor signaling to cardiac ischemia/reperfusion injury. Shock. 2010;34:548–557.

169.

Wang

Kristan

Hao

. A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol. 2000;164:4340–4347.

170.

Ward

Anver

Haines

. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab Anim Sci. 1996;46:15–20.

171.

Watters

Kenny

O'Neill

. Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol Cell Biol. 2007;85:411–419.

172.

Weiner

da Cunha

Quintana

. Oral tolerance. Immunol Rev. 2011;241:241–259.

173.

Wetsel

Fleischer

Haviland

. Deficiency of the murine fifth complement component (C5): a 2-base pair gene deletion in a 5'-exon. J Biol Chem. 1990;265:2435–2440.

174.

Wieland

van Lieshout

Hoogendijk

. Host defence during Klebsiella pneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2. Eur Respir J. 2010;37:848–857.

175.

Williams

Bradley

Smith

. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol. 2004;172:567–576.

176.

Williams

Ricchetti

Sarma

. Interleukin-10 suppression of myeloid cell activation--a continuing puzzle. Immunology. 2004;113:281–292.

177.

Witherden

Havran

. Costimulating epithelial gammadelta T cells. Cell Cycle. 2010;10:4–5.

178.

Witherden

Havran

. Molecular aspects of epithelial gammadelta T cell regulation. Trends Immunol. 2011;32:265–271.

179.

Woods

Frelinger

Warrack

. Mouse genetic locus Lps influences susceptibility to Neisseria meningitidis infection. Infect Immun. 1988;56:1950–1955.

180.

Yamamoto

Okubo

Klein

. Binding of Legionella pneumophila to macrophages increases cellular cytokine mRNA. Infect Immun. 1994;62:3947–3956.

181.

Yamasaki

Ishikawa

Sakuma

. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol. 2008;9:1179–1188.

182.

Yee

Yao

. Cathepsin E: a novel target for regulation by class II transactivator. J Immunol. 2004;172:5528–5534.

183.

Yoshimoto

Bendelac

Watson

. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science. 1995;270:1845–1847.

184.

Yung Yu

Yang

Blanchong

. The human and mouse MHC class III region: a parade of 21 genes at the centromeric segment. Immunol Today. 2000;21:320–328.

185.

Zaidi

Hermann

Herrmann

. Emerging functional roles of cathepsin E. Biochem Biophys Res Commun. 2008;377:327–330.

Immunological Variation Between Inbred Laboratory Mouse Strains

Abstract

Keywords

The Innate Immune System

The Adaptive Immune System

Immune Variation Among Inbred Mouse Strains: Selected Examples

Innate Immunity

Toll-Like Receptors

Complement Factor C5: Hemolytic Complement (Hc)

NOD-Like Receptor-Nlrp (Nalp)

Killer Cell Lectin-Like Receptors (Klra; also called Ly49)

Neuronal Apoptosis Inhibitory Protein

Cathepsin E (Ctse)

Mx1 and Mx2

Oas1b

Candida Albicans Resistance Loci Carg3 and Carg4

D7Mit341 to D7Mit247

Adaptive Immune System Mutations

TH1 vs TH2 responses

T-Cell Receptor β, Variable 8 (Tcrb-V8)

Signaling lymphocyte activation molecule family (Slamf)

Solute Carrier Family 11a Member 1 Slc11a1 (Nramp1, Ity, Lsh, and Bcg)

Major Histocompatibility Complex (MHC) Molecules

Conclusions

Footnotes

Acknowledgements

References