Pathology and Pathogenesis of Immune-Mediated Diseases of Animals

Immune-mediated diseases are diverse in clinical manifestation and pathogenesis, but share a common theme of dysregulation of the normal immune response. Many of these diseases were previously categorized as autoimmune disease implying a direct attack of the immune system on normal tissues in an affected individual. With increased understanding of pathogenesis, especially considering the role of microflora in disease development, the term immune-mediated inflammatory disease has become more widely used. While immune-mediated inflammatory diseases may have variable and sometimes uncertain etiology, they are characterized by a persistent and detrimental immune response. In this special issue of Veterinary Pathology, we present a broad view of immunologic diseases. The publications range from descriptions of naturally occurring diseases, to translational research using animal models of human disease, to in-depth studies of components of the immune response.

Interest in the role of infectious agents and microbial dysbiosis in human immune-mediated diseases has increased over the past decade. ¹² Microbes and parasites fundamentally affect the education and function of the mammalian immune system. ² Idiopathic inflammatory muscle diseases are relatively uncommon and present with heterogeneous features in multiple species. In humans, the presence of autoantibodies and immune cell infiltrates in muscle biopsies suggest immune-mediated pathogenesis. ⁵ The phenomenon of infection and immune dysregulation is important in equine inflammatory myopathies where they have long been associated with Streptococcus equi infection although other bacteria have been implicated. ¹

Durward-Akhurst and Valberg provide an overview of clinical and diagnostic features of acute rhabdomyolysis, infarctive purpura hemorrhagica and immune-mediated myositis in horses. ⁶ While a significant subset of these inflammatory myopathies are associated with a triggering event such as S. equi infection, respiratory viral infection or vaccination, this correlation cannot be made in all cases. Inflammatory myopathies in other species, especially humans and dogs, may also be associated with parasitic infections. ⁷ Infection by the tick-borne protozoa Theileria equi and Babesia caballi, known as equine piroplasmosis, has been associated with muscle atrophy and reduced performance. Pasolini et al investigate myopathy in 16 horses seropositive for equine piroplasms and document inflammatory changes including immune cell infiltrates and increased inflammatory cytokines. ¹⁷ While additional work is required to understand the underlying pathogenic process, the authors provide new information linking the clinical aspects of myopathy to an immune-mediated pathogenesis.

Understanding the role of microflora in pathogenesis, particularly the impact of changes in microflora diversity, can be challenging. Rosa et al used next-generation sequencing to evaluate the skin microbiome in canine sterile granulomatous dermatitis and to support the sterile nature of this inflammatory condition. ¹⁹ Even infectious diseases with identified pathogens can demonstrate a striking level of clinical and pathologic heterogeneity. Mycobacterium tuberculosis infection in humans has long been regarded as either resulting in a latent infection or in active disease, however, there is considerable variability in bacterial characteristics, immune response and lesions within each of these clinical manifestations. ⁴ Comparative pathology and animal model research offer opportunities to understand factors underlying the heterogeneity within individuals of similar clinical classification. In this issue, 2 articles, by Martinot and by Palmer, focus on the structure of the tuberculosis granuloma across species and how a complex interplay of host and bacterial characteristics influence the morphology and the outcome. ^13,16

Animal models are a key component of translational research and drug development for immune-mediated diseases. However, variability of results and predictive value of preclinical animal models is an area of concern. ²¹ There are caveats with cross-species interpretations and the validity of some disease models, as methodological flaws can be a significant problem in translational research studies. ²⁵ The review on strategies for utilizing a variety of specialized techniques for evaluating lung inflammation by Meyerholz et al in this issue addresses this challenge. ¹⁴ In addition, there can be species differences in development of particular disease manifestations. While rodent asthma models lack compelling histologic evidence of airway remodeling, ²⁰ pasture asthma in horses is a naturally occurring condition, which shares airway remodeling characteristics with the human disease as shown by Ferrari, Cooley, Costa, et al. Hence, equine asthma may be a model for appropriate translational questions. ²³

Immune-mediated demyelinating disease generally and multiple sclerosis research in particular have been a focus of concern about the immunologic validity, reproducibility and translatability of existing animal models. ¹¹ Experimental autoimmune encephalomyelitis (EAE) is a commonly used strategy for studying demyelinating disease. However, there are multiple variations on the EAE induction strategy including test species. A review by Stimmer et al provides an in-depth discussion of considerations relevant to EAE studies in nonhuman primates such as rhesus macaques, cynomolgus macaques, and common marmosets. ²² It addresses lesion profiles and heterogeneity in response to adjuvant use strategies.

The need for a more robust understanding of immunologic components of the pathogenic response in naturally occurring disease is an underlying theme of several articles in this issue. Yamada et al characterize progressive glomerulonephropathy in common marmosets and show that deposition of IgM and podocyte alterations occur early in life, suggesting that IgM may be a primary element of the pathogenesis. ²⁷ Additional specificity in describing lymphocyte subsets infiltrating adrenal glands in dogs with primary hypoadrenocorticism, as described by Friedenberg et al, may lay the groundwork for future pathogenesis studies. ⁸ Hepatic mastocytosis in Japanese Black cattle is described for the first time in this issue by Ohfuji. ¹⁵ A relationship between immune cell neoplasia and chronic inflammation is suggested by Matsumoto, Uchida, Nakashima, et al. in an article describing high levels of IgA specific for gliadin and tissue transglutaminase in dogs with intestinal T cell lymphoma. ²⁴ The serologic data combined with known diagnostic challenges of differentiating chronic enteritis from lymphoma lead the authors to hypothesize that intestinal lymphoma arises following chronic antigenic stimulation by dietary proteins in susceptible animals.

There is considerable variability in the understanding of physiologic versus pathologic immune cells and immunologic processes across animal species. The understanding of murine immunology is by far, the most advanced, as much basic immunologic research is performed in this species. However, even in mice, some aspects of the immune system are less well characterized. Mast cell subtypes in the murine intestine represent one area where functional understanding is still limited. Vogel et al describe the association of globule leukocytes, otherwise known as interepithelial mucosal mast cells, with decreased mucosal injury in helminth infections. ²⁶ Bienzle et al describe clinical and pathologic findings of acute leukemia in horses, ³ with the goal of enhancing equine leukemia classification as discussed in the commentary by Raskin. Jeffrey and LeVine measure the impact of neutrophil extracellular traps on thrombosis, ¹⁰ and the immunologic rationale for Dal blood typing in dogs are investigated by Goulet and Blais. ⁹ A review by Richter et al provides an overview on the use of multiplex cytokine assays in dogs, including potential applications in diagnosis and therapy. ¹⁸

Progress in understanding, diagnosing, and treating immune-mediated inflammatory diseases have been progressive and often slow. Advancements in basic immunology and evolving technology lay the groundwork for better understanding and new therapeutic opportunities. Many articles in this issue provide necessary next steps in this process whether by carefully describing immunologic aspects of naturally occurring disease or by going in-depth on a specific immunologic process. Still others directly address translational aspects of immune-mediated inflammatory disease through animal models. Research progress in these areas improves the prospect for accurate diagnosis and eventual therapeutic interventions in a variety of immune-mediated diseases across a number of species.