G D Chazenbalk

Bio: G D Chazenbalk is an academic researcher from Veterans Health Administration. The author has contributed to research in topics: Antibody & Autoantibody. The author has an hindex of 1, co-authored 1 publications receiving 135 citations.

Human organ-specific autoimmune disease. Molecular cloning and expression of an autoantibody gene repertoire for a major autoantigen reveals an antigenic immunodominant region and restricted immunoglobulin gene usage in the target organ.

Abstract: The most common organ-specific autoimmune disease in humans involves the thyroid. Autoantibodies against thyroid peroxidase (TPO) are present in the sera of virtually all patients with active disease. We report the molecular cloning of the genes for 30 high-affinity, IgG-class human autoantibodies to TPO from thyroid-infiltrating B cells. Analysis of the putative germline genes used for the TPO human autoantibodies suggests the use of only five different H and L chain combinations involving four H chains and three L chains. In addition, the same combination of H and L chains was found in multiple patients. The F(ab) proteins expressed by these genes define two major, closely associated domains (A and B) in an immunodominant region on TPO. These A and B domains contain the binding sites of approximately 80% of IgG-class TPO autoantibodies in the sera of patients with autoimmune thyroid disease. The present information permits analysis, not previously possible, of the relationship between autoantibody H and L chain genes and the antigenic domains on an autoantigen. Our data, obtained using target organ-derived autoantibodies, indicate that there is restriction in H and L chain usage in relation to the interaction with specific antigenic domains in human, organ-specific autoimmune disease.

Autoimmune thyroid disease: further developments in our understanding

Abstract: The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Human antibodies from combinatorial libraries.

Abstract: Publisher Summary Combinatorial antibodies will play a significant role in the design of vaccines and new antiviral agents. Antibodies may also provide a way of determining receptor function in vivo and serve as templates for the design of small molecules. Combinatorial antibodies have been shown to provide an accurate functional reflection of the natural response as demonstrated by the ability of cloned antibodies to compete with serum antibodies for binding antigens. Combinatorial antibodies also provide a useful (if somewhat incomplete) guide to the molecular biology of the response. With its ability to provide large numbers of human antibodies directed against a single antigen, the combinatorial approach allows for the rapid assessment of immune dominant as well as neutralizing epitopes in the context of the human response. This information should be utilized in the future to guide the design of more effective vaccines. The new-found ability to generate human antibodies and to evolve their specificities and affinities, ex vivo promises increased the use of this class of molecules in the service of human health.

Autoimmune Thyroid Disease

Abstract: Autoimmune thyroid disease is common and was the first autoimmune disease to be described, based on observations in animals immunized with thyroid extract and adjuvant. There are several different clinical presentations which, although being distinctive, share some common features in terms of genetic susceptibility, environmental factors that predispose to disease and pathogenic features such as the presence of autoantibodies against thyroglobulin and thyroid peroxidase. In autoimmune hypothyroidism, the thyroid is initially enlarged due to the presence of a marked lymphocytic infiltrate; this phase is followed by fibrosis, atrophy of the gland, and failure to synthesize normal levels of thyroid hormones. The main etiological factors in this process are cytotoxic T cells and an intrathyroidal proinflammatory state created by local cytokine release. Humoral autoimmunity may contribute through the action of thyroid-stimulating hormone (TSH) receptor-blocking autoantibodies or through the activation of complement and antibody-dependent NK cell-mediated cytotoxicity. In Graves' disease, thyroid overactivity is caused by autoantibodies which stimulate the TSH receptor. T cells which recognize the receptor also localize to the orbit in many of these patients, as a subpopulation of fibroblasts at this location also express the receptor; the cytokines produced by these T cells in turn leads to the clinical features of Graves' ophthalmopathy.

Autoimmune thyroid disease: propagation and progression

Abstract: Autoimmune thyroid disease is the archetype for organ-specific autoimmune disorders. Progress in treating these disorders lies in improvements of our understanding of the predisposing factors responsible, the mechanisms responsible for progression of disease, and the interaction between thyroid antigens and the immune system at the level of the T cell and antibody. In common with other autoimmune diseases, genetic, environmental and endogenous factors are required in an appropriate combination to initiate thyroid autoimmunity. At present the only genetic factors which have been confirmed lie in the HLA complex and CTLA-4 or a closely linked gene. Identifying other predisposing genes will require large-scale family studies, or further insights into likely candidate genes. A number of environmental factors are known to predispose to autoimmune thyroid disease, including smoking, stress and iodine intake, while immunomodulatory treatments are revealing new pathways for disease emergence. The thyroid cell itself appears to play a major role in disease progression, interacting with the immune system through expression of a number of immunologically active molecules including HLA class I and II, adhesion molecules, cytokines, CD40 and complement regulatory proteins. New techniques, in particular phage display libraries, are providing the methods with which to identify autoantibody diversity in autoimmune thyroid disease and to provide tools for mapping autoantigenic epitopes. Application of these techniques is likely to lead to an understanding of how TSH receptor antibodies interact with the receptor to cause Graves' disease and also to the identification of novel orbital autoantigens in thyroid-associated ophthalmopathy.