Exam 15: Autoimmunity and Transplantation

In some cases, a transient autoimmune process can occur as a result of an infection. This may be due to molecular mimicry between the pathogen and a self-antigen, or to the release of normally sequestered self-antigens due to tissue damage from the infection. An important factor leading to these autoreactive immune responses is the activation of dendritic cells by the infection-induced inflammation. Once the infection is resolved, this inflammation will also subside. As a consequence, autoreactive T cells may no longer receive sufficient signals to promote their activation, causing a remission in the autoimmune symptoms. One important change in antigen-presenting dendritic cells during an infection that would contribute to the activation of normally self-tolerant self-reactive T cells is:

Polymorphisms in the IL-2R $\alpha$ chain gene are associated with multiple autoimmune diseases, including type 1 diabetes, vitiligo, multiple sclerosis, Crohn's disease, autoimmune thyroiditis, and juvenile arthritis. One hypothesis for this striking list of disease associations with polymorphisms in the IL-2R $\alpha$ chain gene is that these alterations affect the function of FoxP3+ regulatory CD4 T cells. If this was the case, one would expect that disease-associated alleles of the IL-2R $\alpha$ chain gene would:

Some early studies aimed at deciphering the mechanisms involved in immunological tolerance, and its breakdown in cases of autoimmune disease, were based on generating transgenic mice that constitutively expressed a viral protein in the $\beta$ -islet cells of the pancreas. These mice were crossed to transgenic mice expressing a T-cell receptor specific for MHC class I bound to a peptide of this viral protein. The double transgenic mice generated large numbers of CD8 T cells capable of recognizing this viral antigen on $\beta$ -islet cells, yet the mice never spontaneously developed type I diabetes, a disease in which $\beta$ -islet cells are destroyed by T cells. This lack of response most likely reflects:

Systemic lupus erythematosis (SLE) is an autoimmune disease characterized by the development of autoantibodies specific for DNA and other nuclear antigens. Patients with SLE show a wide variety of symptoms that include anemia, skin rashes, joint and muscle pain, heart problems, and kidney damage. This is considered a systemic autoimmune disease because:

A mouse model of spontaneous rheumatoid arthritis (RA) was fortuitously discovered when a T-cell receptor transgenic mouse line made in C57BL/6 mice (KRN) was crossed to the NOD strain. These mice, known as KxN, developed RA beginning at about 4-5 weeks of age. The disease symptoms included joint swelling, infiltration of inflammatory cells, with eventual deterioration of bone and cartilage. As a first experiment to determine the mechanism leading to this autoimmune response, KRN⁺ CD4 T cells were isolated from C57BL/6 mice and were stimulated in vitro with purified APCs from wild-type C57BL/6 mice, NOD mice, or C57BL/6 mice expressing the NOD MHC class II allele, I-A^g7 (C57BL/6-A^g7). After three days, the T cultures were pulsed with ³H-thymidine, and cpm incorporated were measured to assess T cell proliferation, as shown in Figure Q3)31)A. Furthermore, the CD4 T cell compartment in KxN mice was examined, and compared to KRN-transgenic negative littermate control mice. Whereas the littermate controls generally had 16-22% CD4 T cells in their spleens, KxN had 5-7% CD4 T cells, all of which expressed the KRN T-cell receptor. a) What do these data indicate about the mechanism(s) of self-tolerance acting on KRN T-cell receptor-positive CD4 T cells in the KxN mice? receptor recognized a peptide of a ubiquitous self-antigen (glucose-6-phosphate isomerase; GPI) bound to the NOD MHC class II allele, I-A^g7. In addition, the sera of the KxN mice were found to have circulating IgG antibodies to GPI. To address whether T cells or B cells were required for autoimmune disease initiation and/or progression, a series of studies were performed. In one study, CD4 T cells were eliminated in young KxN mice by injection of a cell-depleting anti-CD4 antibody (or an isotype control antibody), and disease progression was monitored. In a second study, anti-CD4 antibody was injected into KxN mice after disease symptoms had already appeared. The mice were then monitored for the ensuing several weeks. In a third study, KxN mice were crossed to a line of mice with a mutation in the immunoglobulin locus that blocks all B cell development. KxN B-cell-deficient mice were then compared to KxN B-cell-sufficient mice for the development of RA symptoms. These data are shown in Figure. b) What do these data indicate about the role of T cells, B cells, and antibodies in the development and disease progression of RA in this mouse model? In a next experiment, sera from KxN arthritic mice or non-arthritic control mice were isolated, and injected into RAG-deficient recipients. Recipient mice were then monitored for clinical disease, and were scored on a scale of 1-5 every 3 days, as shown in Figure ; 1 = mildest disease to 5 = severe disease. c) What do these data, together with the data shown above, indicate about the pathogenic mechanisms operating in this model of RA? In a final set of studies, potential effector mechanisms resulting in joint inflammation and destruction were examined. Serum from KxN arthritic mice was injected into Rag-deficient recipients that were lacking expression of the complement component C3 or the neutrophil chemokine receptor CXCR2. Disease progression was monitored after serum injection and compared to that seen following KxN serum injection into control Rag-deficient recipients as shown in . d) What do these data indicate about the disease mechanism in this model of RA? e) Given all of these data, what is the likely role of the KRN⁺ CD4 T cells in this disease model?

A mouse model for multiple sclerosis is induced by immunizing mice with murine central nervous system proteins mixed with Complete Freund's adjuvant. This adjuvant contains components that stimulate both TLR2 and TLR4. The adjuvant is essential to the development of autoimmunity because:

Rheumatoid arthritis is often classified as a T-cell-mediated autoimmune disease, where disease symptoms are caused by chronic inflammation in the joints. Yet approximately 50% of rheumatoid arthritis patients that were treated with a B-cell depleting antibody (rituximab, anti-CD20 antibody) showed significant improvement in their disease symptoms. This improvement following rituximab treatment is due to:

10) A mouse model for autoimmune hemolytic anemia can be transferred to naive mice by a single injection of anti-red blood cell IgG antibodies. However, the disease is prevented if recipient mice lack IgG-binding Fc receptors. These data indicate:

A mouse model for type 1 diabetes, the NOD mouse, has a well-described sex bias in the incidence and rate of diabetes onset. Female NOD mice are about twofold more likely to become diabetic, and do so on average about six-weeks earlier than male NOD mice. Recent studies have shown that a large component of this sex bias is due to differences in the intestinal microbiota between male and female NOD mice. In fact, colonization of young female NOD mice with male microbiota reduced the incidence and time to onset of diabetes in the transplanted mice, resulting in a disease course resembling that of the typical male NOD mice. These data indicate that:

Genetic linkage studies have identified numerous genes in which certain polymorphisms are associated with a predisposition to autoimmune disease. Yet in most cases, the effects of individual genetic polymorphisms are very small, with each one being linked to a very modest effect on disease incidence. This indicates that:

GWAS data have identified multiple genes associated with autoimmune diseases. These data indicate the presence of polymorphisms in the gene sequence among the human population, where certain alleles are increased among patients with a particular autoimmune disease. One example is the gene encoding the IL-2R $\alpha$ chain. Interestingly, several of the polymorphisms in this gene that are found to be increased in patients with multiple sclerosis do not alter the protein coding sequence, and therefore do not result in differences in the amino acid sequence of the IL-2R $\alpha$ chain protein between healthy individuals and those with the disease-associated allele. Instead, it is likely that these allelic differences in the IL-2R $\alpha$ chain locus: