Avian scleroderma: Evidence for qualitative and quantitative T cell defects

doi:10.1016/0896-8411(92)90142-D

Journal of Autoimmunity

Volume 5, Issue 3, June 1992, Pages 261-276

https://doi.org/10.1016/0896-8411(92)90142-D Get rights and content

Abstract

T cell activation is dependent upon calcium influx and protein kinase C activation, with subsequent lymphocyte proliferation dependent upon IL-2. Abnormalities in T cell proliferation, including abnormal calcium influx and defective protein kinase C activation, have been identified in aged mice and humans and many autoimmune diseases including diabetes, lupus and scleroderma. Since UCD line 200 chickens, which spontaneously develop a scleroderma-like disease, have both thymic defects and a diminished peripheral blood lymphocyte response to IL-2, we have further investigated T cell function in these birds. Interestingly, line 200 T cells respond poorly in vitro to a variety of diversely acting T cell mitogens including concanavalin A, phytohemagglutinin and anti-chicken CD3 monoclonal antibody. Moreover, they do not respond well even to phorbol myristate acetate in conjunction with ionomycin. Addition of exogenous IL-2-containing supernatant concurrently with mitogenic stimulation also had no significant effect. Analysis of intracellular free calcium demonstrated that the lymphocytes from diseased birds had a reduced influx of calcium (or release for intracellular stores) following stimulation. These data clearly reflect a unique defect in T cell activation associated with avian scleroderma. Analysis of chicken CD3, CD4 and CD8 expression revealed a 39% decrease in peripheral blood CD4⁺ cells in scleroderma birds, although this decrease was not sufficient to explain the 80–90% decrease observed in proliferation assays and calcium influx. Our data support the hypothesis that avian scleroderma is mediated via abnormal function of lymphocyte co-stimulatory molecules or intracellular calcium regulators.

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Multifactorial, noncommunicable diseases such as autoimmune diseases develop postnatally in susceptible individuals. Susceptibility involves multiple genes, and disease expression appears to be driven by endogenous and/or exogenous environmental factors. Disorders presenting with immune-mediated pathology and possible target cell-specific autoimmune responses are emerging in poultry production including lameness, wooden breast, and various skin, metabolic, pulmonary, gastrointestinal reproductive disorders. Research lines of chickens with spontaneously occurring autoimmune diseases, such as vitiligo in the Smyth line, Hashimoto’s thyroiditis in the Obese strain, and scleroderma in the UCD 200/206 lines, are excellent animal models to study multifactorial diseases—for both veterinary and human medicine. These lines of chickens have made many highly relevant contributions to our understanding of autoimmune diseases, because of the spontaneous, predictable, and high incidence of disease expression, the identification of environmental triggers, and the ability to study the etiology, pathology, and progression of the disorders.
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Citation Excerpt :
In vitro, UCD‐200 peripheral blood T cells show a significantly decreased mitogen‐induced proliferation rate associated with a decreased capacity to produce IL‐2 and to express IL‐2 receptors compared with healthy control chickens. In contrast to the deficient in vitro IL‐2 production, the sera of UCD‐200 chickens contain significantly higher levels of IL‐2 bioactivity (Gruschwitz et al., 1991; Wilson et al., 1992). The in vitro vs in vivo discrepancy might be explained by a state of preactivation of peripheral T lymphocytes, either by autoantigens or by nonspecific signals resulting in a transient exhaustion of IL‐2 secretion that becomes effective in vitro.
Autoimmune diseases in human patients only become clinically manifest when the disease process has developed to a stage where functional compensation by the afflicted organ or system is not possible anymore. In order to understand the initial etiologic and pathogenic events that are generally not yet accessible in humans, appropriate animal models are required. In this respect, spontaneously developing models—albeit rare—reflect the situation in humans much more closely than experimentally induced models, including knockout and transgenic mice. The present chapter describes three spontaneous chicken models for human autoimmune diseases, the Obese strain (OS) with a Hashimoto‐like autoimmune thyroiditis, the University of California at Davis lines 200 and 206 (UCD‐200 and ‐206) with a scleroderma‐like disease, and the amelanotic Smyth line with a vitiligo‐like syndrome (SLV). Special emphasis is given to the new opportunities to unravel the genetic basis of these diseases in view of the recently completed sequencing of the chicken genome.
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Systemic Sclerosis (SSc) is a connective tissue disease affecting the skin and internal organs. Retinopathy has been described in patients with SSc, but cannot be distinguished from secondary changes due to concomitant hypertension. UCD 200 chickens, a well-established animal model for SSc, were used in this study to investigate the posterior ocular segment for manifestations of SSc. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling was applied to detect endothelial cell (EC) apoptosis, a condition previously shown to represent the first step in SSc pathogenesis in humans and to be present in the skin and the involved internal organs of UCD 200 chickens in the acute stage. Our study showed a complete absence of EC apoptosis in the pecten and choroidal vessels of UCD 200 chickens in the acute stage. Ophthalmoscopy, biomicroscopy and histology revealed normal structures of the pecten, retina and choroid in the chronic stage. In summary, we showed that there is no primary involvement of the posterior ocular segment in avian SSc. SSc of UCD 200 chickens closely mimics human SSc, presenting all the clinical, serological and histological disease manifestations seen in the human counterpart. Therefore, our data raise serious doubts about primary posterior ocular involvement in human SSc. However, fundal examinations in patients with SSc may have their justification for assessment of hypertensive retinopathy.
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Avian scleroderma: Evidence for qualitative and quantitative T cell defects

Abstract

Adv. Immunol.

Clin. Immunol. Immunopathol.

J. Autoimmunity

Clin. Immunol. Immunopathol.

J. Immunol. Methods

J. Biol. Chem.

J. Autoimmunity

Dermatol. Clin.

J. Autoimmunity

Immunol. Today

Triggering of the T3-Ti antigen-receptor complex results in clonal T-cell proliferation through an interleukin 2-dependent autocrine pathway

Development and function of T cells in mice rendered deficient by gene targeting

Nature

Age-related deficiency in intracellular calcium response to anti-CD3 or concanavalin A in murine T-cell subsets

J. Gerontol.

Diminished calcium signal generation in subsets of T lymphocytes that predominate in old mice

J. Gerontol.

Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis

J. Immunol.

Characterization of a spontaneous disease of White Leghorn chickens resembling progressive systemic sclerosis (scleroderma)

J. Exp. Med.

Diversity of autoantibodies in avian scleroderma: An inherited fibrotic disease of white leghorn chickens

J. Clin. Invest.

Serial observations and definition of mononuclear cell infiltrates in avian scleroderma

Arthritis Rheum

Identification of T cells in early dermal infiltrates in avian scleroderma

Arthritis Rheum

Genetic control of avian scleroderma

Immunogenetics

Syngeneic inbred lines of chickens and their uses in immunogenetics

Adv. Exp. Biol.

Identification of a T3/T cell receptor complex in chickens

J. Exp. Med.

Attempt to detect recombination between B-F and B-L genes within the chicken B complex by serological typing, in vitro MLR, and RFLP analyses

Immunogenetics