General Session 3: Acquired Immunity

Abstract

Session 3 of the Toxicologic Pathology and the Immune System Symposium, presented as part of the 30th Annual Symposium of the Society of Toxicologic Pathology in 2011, focused on the biological advances in control of selected cellular and secretory components of acquired immunity. Acquired immunity goes beyond innate immunity to provide controlled recognition and memory for specific antigenic challenges. Predominately involving activation of T and B lymphocytes, the resulting cellular- and secretory-mediated activity provides immediate and long-term host defenses to antigenic challenge. This session highlighted the biological advances in function and dysfunction of acquired immunity through regulatory T cells, the pathophysiology of effector cells and secretory molecules in immunosuppression, allergic inflammatory disease, and dysregulation that leads to loss of tolerance and autoimmune disease. A brief overview of major concepts in acquired immunity and summaries of the above themes are covered herein, and discussions of these themes are covered in greater detail in this issue of Toxicologic Pathology.

Concepts of Acquired Immunity

Acquired immunity, also known as adaptive or specific immunity, provides controlled recognition and memory for specific antigenic challenges. This immune response pathway uses cell- and humoral-mediated components including circulating and tissue cells (T and B cells, γδ T cells, dendritic cells, natural killer [NK] cells, and phagocytes) and secretions (cytokines, antibodies, products of phagocytosis, acute phase reactants, complement, and hormones). Together, these components provide immediate and long-term host immunity through tightly regulated receptor-ligand modulation of cells and secretions. While once thought critical to controlled immune responsiveness, discrimination of self from nonself or foreign antigens is relinquishing its prominence to a Danger model, whereby tissue injury rather than nonself signals the immune response. As the cells, secretions, and self versus nonself aspects that regulate acquired immunity are also involved in the regulation of innate immunity, these immune pathways are complementary and not discrete. Compared with innate immunity, acquired immunity is typified by a specific and systemic response to a pathogen or antigen, a delay between exposure and maximal response, and immunological memory.

Despite tight regulation, dysfunction of acquired immunity is an important clinical problem involving both deficient and exaggerated responses. Conversely, intentional and controlled modulation of acquired immunity is sought during vaccination, transfusions, and prevention of transplantation organ rejection. Thus, both the cellular and secretory components and the regulatory arms of acquired immunity are important clinical targets for pharmacological intervention.

Acquired immunity is a multifaceted and complex system, and the reader is referred to other articles in this issue of Toxicologic Pathology and current textbooks for details on basic and advanced immunology. The complexity of immunology precluded presenting anything other than selected topics in this session. Thus, the presentations in Session 3: Acquired Immunity focused only on the emerging field of regulatory T cells and an overview of the immunobiology related to syndromes of immunodeficiency and exaggerated immunity, including allergic inflammatory disease and autoimmunity.

Summary of Session 3: Acquired Immunity

The first presentation by Dr. Richard Peterson of GlaxoSmithKline (Research Triangle Park, NC) reviewed the pathobiology of regulatory T cells. He discussed the features of regulatory T cells (Tregs), the biology and deficiency states of Foxp3, the role of Tregs in disease, and Tregs as a therapeutic target. Tregs are a heterogenous population of natural and inducible lymphocytes critical to multiple regulatory pathways, including elimination of autoreactive T cells, induction of tolerance, and downregulation of inflammation. The molecular marker and lineage-specific identifier of natural (thymic) Treg is CD4⁺CD25⁺Foxp3⁺, and cytokines and growth factors induce other Treg types, including T_r1, T_H3 (Foxp3⁺), CD8⁺, a double-negative (CD3⁺CD4⁻CD25⁻), and an NKT_reg cell (NK1.1⁺Vα14⁺). Defects in the FOXP3 gene and its product scurfin are the cause of immunodeficiency polyendocrinopathy, enteropathy, and X-linked syndrome, also known as X-linked autoimmunity-immunodeficiency syndrome in humans. A comparable fatal condition occurs in scurfy mice (B.Cg-Foxp3^sf ), where cytokines are elevated, and CD4⁺ and other inflammatory cells infiltrate into lymphoid tissues, the subcutis, and multiple organs due to the lack of Tregs. Via the secretion of TGFβ, T_H3 Tregs inversely regulate an effector population of proinflammatory T_H17 cells that are associated with allergic and autoimmune disease. Tregs are also involved in oral tolerance via the mucosa (inhibition enhances inflammatory bowel disease in mouse models), infectious diseases (microbes can downregulate Tregs), and cancer. In addition, Tregs are critical to successful organ transplantation and in immune tolerance in pregnancy. Consequently, modulation of Tregs by numerous immunoregulatory molecules is an emerging area of immunotherapeutic intervention.

The second presentation by Dr. Curtis Maier of GlaxoSmithKline (King of Prussia, PA) presented basic concepts and recent advances in immunosuppression by first reviewing normal T- and B-cell function and regulation and how adverse immunosuppression can be difficult to detect in the face of normal fluctuations in immune responses. Primary deficiencies based in defects in lymphoid development (e.g., DiGeorge syndrome) or impaired lymphoid signaling (e.g., CD3), immunosuppressive drugs used for organ transplantation (e.g., rapamycin), and immunoregulatory monoclonal molecules (e.g., anti-VLA4) were reviewed to demonstrate molecular pathways critical to immunocompetence. These pathways target cell proliferation, signaling, or activation and migration, and include the IL-12–IL-23–IFNγ axis, the common gamma chain of IL-2R, Ca⁺² flux and signal transduction, and terminal B-cell differentiation in germinal centers. Genetic and acquired deficiency states result in an increased risk for malignancies and infections, typically viral, fungal, and intracellular bacterial infections predominating, with T-cell suppression and sinopulmonary bacterial infections predominating with B-cell suppression. Intentional and unintentional pharmacologic modulation of these pathways can alter T-, B-, or both T- and B-cell responses, leading to immunosuppression, which may be difficult to detect without careful evaluation of the pharmacodynamics, toxicology, toxicologic pathology outcomes, immunophenotyping, and functional immunotoxicity testing.

The third presentation by Dr. Cara Williams of Pfizer Research (Cambridge, MA) focused on cytokine pathways in allergic disease. The T_H2-type cytokine, IL-5, predominates in mild to moderate allergic asthma, but therapeutic inhibition has not provided substantive relief in asthmatics. Other T_H2 cytokines such as IL-4 and IL-13 are thought to be critical to the full manifestation of allergic inflammatory disease through the recruitment and activation of proinflammatory leukocytes, mucus, and IgE production; airway hyperresponsiveness; and chronic profibrotic and remodeling events. Allergic triggers influence the T_H2/T_H1/T_H17 cytokine balance, and understanding of the selective activity of IL-4 and IL-13 during different phases of asthma could be pivotal to appropriately blocking harmful cytokine activity. Using the mouse OVA model of asthma, the consequences of selective blocking during the sensitization and effector phases was reviewed. Blocking IL-4 or IL-13 during the sensitization phase reduces inflammation, but IL-4 and not IL-13 blockade reduces IgE, IgG₁, and IL-13 but not IL-5. Blockade of IL-13 but not IL-4 effectively blocks all inflammatory activity during the effector phase. Conversely, using a model of cutaneous allergy, the absence of IL-4 attenuated the late-phase allergic response, whereas lack of IL-13 did not. A brief description of other cytokines that have been suspected to be involved in the pathogenesis of allergic airway inflammation was provided. These included thymic stromal lymphopoietin, a recently identified cytokine that may play an important role in T_H2 switching, and IL-33, which can induce cytokine release from mast cells and induce eosinophil degranulation. Thus, targeting early innate-type cytokines may provide therapeutic benefit for allergic disease.

The final presentation by Dr. Brad Bolon of GEMpath, Inc. (Longmont, CO) reviewed the biology of immune tolerance and its dysfunction in autoimmunity. The immune system is capable of making antiself antibodies that normally do not injure self-tissues. A breakdown in this self-tolerance results in autoimmune disease. Self-tolerance is regulated at multiple levels, including central tolerance (preactivation deletion in the bone marrow and thymus), antigenic segregation by a physical barrier to peripheral lymphoid organs, clonal anergy due to insufficient co-stimulation, clonal deletion to eliminate autoreactive clones, clonal suppression by Tregs, and cytokine reduction by T-cell differentiation to T_H2 phenotype. Tolerance is further modulated by environmental factors (e.g., infections, ultraviolet light, and xenobiotics) and hormonal influences. Mechanisms proposed to account for loss of self-tolerance include molecular mimicry between self-antigens and bacterial or viral proteins, molecular modification of self-antigens by haptens, unmasking of barrier-protected antigens, genetic predisposition, forbidden clones, altered T_H populations (particularly CD4⁺ and CD17⁺ cells), and loss of Treg activity. Autoimmune diseases are mediated by both the innate arm of the immune system (via Toll-like receptors 3, 7, and 9) and the acquired branches (with critical roles for the T_H1 phenotype, IL-17–producing T cells [T_H17 phenotype], and CD8+ T cells). An imbalance in the local levels of proinflammatory and anti-inflammatory molecules is the proposed pathogenesis of autoimmunity. A difference in the immunopathogenesis of autoimmunity was described for the spectrum of inflammatory bowel disease in humans, where T cells and macrophages predominate in the Crohn’s disease phenotype while B cells and neutrophils predominate in the ulcerative colitis phenotype. Autoimmune disease results from many distinct mechanisms, exemplified in inflammatory bowel disease of mice by improper immune cell activation (IL-10^{− /−}), loss of barrier integrity (Mdr1^{− /−}), and pathogenic bacteria (Citrobacter sp.). Although upregulation of proinflammatory molecules and downregulation of anti-inflammatory molecules are frequent sequelae of autoimmune diseases, the lack of a common profile across diseases limits therapeutic targeting of these molecules. Rather, broad targets such as prevention of T-cell activation (using antagonists of T-cell receptor and/or co-stimulatory molecules), reduction of T- or B-cell numbers, inhibition of inflammation (via blockade of cytokines and/or cytokine receptors, or inhibition of leukocyte migration), and reinduction of tolerance are currently favored for treatment of clinically important Crohn’s disease, multiple sclerosis, psoriasis, and rheumatoid arthritis.