Autoimmune Diseases : Biological Basis and Methods of Detection - Coursework Example

Autoimmune Diseases: Biological Basis and Methods of Detection and Study Introduction Autoimmune diseases are defined as “a clinical syndrome caused by the activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause” (Davidson & Diamond, 2001: p.345). Autoimmunity is characterized by a misdirected immune response in which the body’s defenses become self-destructive. Autoimmune diseases are not transmitted from one person to another. The process of autoimmunity is related to genes or a combination of genes, hormones, and environmental stimuli. Individuals with specific genes or gene combinations are at a higher risk for developing autoimmune disorders which may be triggered by outside stimuli such as “sun exposure, infection, drugs or pregnancy” (Harold, 2008: 437). Thesis statement: The purpose of this paper is to discuss autoimmune diseases, their biological basis, methods of detection and study. Discussion Many autoimmune diseases are characterized by B-cell hyperactivity, marked by proliferation of B cells and autoantibodies and by hypergammaglobulinemia. B-cell hyperactivity is probably related to T-cell abnormalities, but the molecular basis for autoimmunity is poorly understood. Hormonal and genetic factors strongly influence the incidence of autoimmune disorders; for example lupus erythematosus predominantly affects females of child bearing age. “Certain HLA (histocompatibility leukocyte antigen) haplotypes are associated with an increased risk of specific autoimmune disorders” (Harold, 2008: 437). Autoimmune disorders may not follow a clear pattern of symptoms; therefore a definitive diagnosis may be delayed. Diagnosis may rely on the patient’s medical history, family history, physical examination, including signs and symptoms and laboratory tests. Autoantibodies are usually found with such disorders as rheumatoid arthritis or systemic lupus erythematosus. However, confusion may result because individuals with these disorders may have false negative results to laboratory tests. Treatment for autoimmune disorders focuses on relieving symptoms, preserving organ function, and providing medication that can target the immune system such as cyclophosphamide and cyclosporine. Autoimmune and immunological disorders are being further researched (Harold, 2008: 438). In most autoimmune diseases, mutligenic factors play a significant role in pathogenesis. Considerable progress has been made in identifying thesw genetic factors, many of which are located outside the major histocompatibility complex. Most autoimmune diseases are multigenic disorders in which genes of the major histocompatibility complex (MHC) play an important role. To define the other genes of importance several genetic methods can be used. The search for non-HLA genes by investigating affected sib-pairs has been advocated, although large numbers are needed to allow significant conclusions. A subsequent approach is the typing of patients in isolated populations. Patients are often not aware that they are relatives of other patients in the same population. In this case, even small samples contribute to mapping of the involved genes. Finally, patients versus controls have to be studied to estimate the relative risk of the distinct genes (Feltkamp et al, 1999). Biological Basis: Genetic Risk Factors for Autoimmune Diseases Genetics and molecular technology have greatly increased understanding of the cellular processes leading to autoimmunity, and this knowledge is being used in clinical applications. The role of B cells in autoimmune disease is considered to be significant. Although autoantibodies are characteristic of many autoimmune diseases, their involvement in the pathological process has long been debated. Recent technology for probing autoantibody structure, together with an increased understanding of B cell activity have shed new light on the role of B cells in autoimmunity. Additionally, the study of ectopic germinal centre sites has revealed disease associated cellular interactions operating at the local level. There is interest in new clinical approaches to diseases, where treatment has been limited to relieving symptoms, autoimmunity from basic biology to clinical applications (Stevenson & Natvig, 1999). . Normal B-cell behaviour Normal B-cell differentiation is essential to prepare for greater understanding of the regulary points that have been evaded in autoimmune disease. It is clear that of the B-cells that make autoantibodies, some of them are directly pathological and should have been eliminated or tolerized. Most pathological autoantibodies have undergone isotype switching to IgG. The nature of theIgG subclass will influence the pathological outcome, and is controlled by CD41 T-cell subsets and their cytokines. However, “the view of the effects of exogenous cytokines was challenged and new data was presented indicating local transfer of cytokines between B and T cells” (Stevenson & Natvig, 1999: 1). Autoantibody Recognition Sites Immunogenetic approaches have facilitated the probing of autoantibody structures. Phage expression of defined antibodies has allowed manipulation of the amino acid sequence in order to identify those amino acids that are important for recognition. In studies of primary biliary cirrhosis (PBC), the hallmark of which is anti-mitochondrial antibodies, removal of somatic mutations from the antibodies changed the specicity from one side of the target antigen to another. This suggests that the triggering epitope in PBC differs from the target epitope involved in the developed disease. In mature autoantibodies from SLE or rheumatoid arthritis, the contribution of individual amino acids to antibody recognition, or to expression of idiotopes, can now be mapped. This information may be relevant for developing appropriate treatment. Transforming Growth Factor b1 (TGF-b1) TGF-b1 is an important regulator of immune cell differentiation and function. The progressive inflammatory process found in TGF-b1 knockout (KO) mice is associated with several manifestations of autoimmunity. In vivo treatment with anti-CD4 or anti-CD8 monoclonal antibodies reduces inflammation and increases survival. Crossing the “TGF-b1-KO mice into an MHC class II-KO background completely cancels the autoimmune inflammatory symptoms. Additionally, crossing the TGF-bi-KO mice into a background deficient in cyclin-dependent kinase inhibitor p21 reversed the inflammatory process. Normally p21 is expressed in activated lymphocytes and it protects against apoptosis. Expression of the autoimmune phenotype is dependent on T-cell function and on a defective apoptosis (Feltkamp et al, 1999). The Role of Cytokines Cytokines provide a network of effector molecules that connect cells of the immune system and cells of the different target tissues in an intricate web of responses. Many of the most significant interactions in this network occur in microenvironments that may be isolated from the general circulation. Uniques tissue specific properties may result in immune cells of identical function having very different effects. In many cases, the outcome may relate to how positive feedback for the secretion of specific cytokines becomes established (Kuchroo et al, 2002). In autoimmune disease pathology seems to be induced mainly by T cells that have developed in environments that promote Th1 differentiation, even though Th1 effector cytokines such as IFN-y and TNF-x have clearly been shown to be redundant to the development of disease. In experimental models it has been shown that blocking IL-12 is almost always effective in preventing disease. However, how much of this effectiveness depends on intervening when disease is being induced remains to be determined. IL-10 and TGF-B are both powerful immunoregulatory cytokines which may be exploited in therapy in the future. One goal with Cytokines is developing techniques to target their delivery in a tissue specific fashion. This ambition reaches its peak with aspirations towards antigen/organ-specific immunomodulatory therapy. This goal can be achieved only through “a close understanding of the complex interplay between immune cells, tissue mico-environment, and the network of cytokines that link the two” (Kuchroo et al, 2002: 406). Classification of Autoimmune Diseases For clinicians, autoimmune diseases are either systemic as in the case of systemic lupus erythematosus or organ-specific as in the case of Type 1 diabetes mellitus. This classification although clinically useful, does not necessarily correspond to a difference in causation. A more useful division distinguishes between diseases in which there is a general alteration in the selection, regulation, or death of T cells or B cells and those in which an aberrant response to a particular antigen, self or foreign, causes autoimmunity. This classification is useful for deciding on a therapy, which may differ according to the pathogenic mechanism. Although this mechanistic classification can be used for animal models, it is difficult to determine whether a human disease is due to a global abnormality in lymphocyte function or an antigen-specific abnormality (Davidson & Diamond, 2001). Methods of Detection and Study Insulin-dependent diabetes mellitus (IDDM): IDDM is determined by a combination of environmental and genetic factors. The major histocompatibility complex (MHC) region contains multiple susceptibility loci including the MHC class II genes (together called IDDM1). In addition, 12 non-HLA linked diabetes susceptibility loci have been found. Another gene modulating the risk of IDDM has been recognized by Moghaddam et al (1997), centromeric to the tumor necrosis factor (TNF) gene. Some class II haplotypes are predisposing for the disease and others are protective. IDDM can be separated into two phases: an inactive insulitis characterized by islet reactive T-cells and autoantibodies but with normal islet function and without clinical symptoms, followed by an invasive insulitis leading to an initially reversible, but later irreversible destruction of b cells. Progression from phase 1 to 2 is relate to class 1 loci. In terms of prognosis, serum antibodies to b cells are still the best predictors for developing IDDM, whereas individuals with DQB 1 0602 never develop the disease (Feltkamp et al, 1999). Multiple Sclerosis: The importance of genetics in multiple sclerosis (MS) has been demonstrated by several studies, as well as by a small number of conjugal MS patients. The offspring of such couples have a risk far above that of children of only one affected parent. In fact, the risk is close to that of monozygotic twins. Approximately 12 regions of the human genome appear to be important for susceptibility for MS. By pooling genetic information obtained in various autoimmune diseases such as MS, IDDM and rheumatoid arthritis it is hoped that genes with an overall importance for autoimmunity might be found. Early indications are that a gene on chromosome 18 is such a common gene. Through an approach termed as genome scavenging, data were sampled from studies on MS and IDDM and it was found that a gene on chromosome 11 associated with both diseases (Feltkamp et al, 1999). Coeliac Disease: In coeliac disease, gliadin in food is recognized by intestinal T cells. This interaction generates IgA autoantibodies that are directed to the endomysium. These antibodies are now known to be specific for tissue transglutaminase. Altered peptide from gliadin act as haptens to generate antibodies to transglutamase. Peptides from gliadin generated in vitro by this enzyme are recognized by gutderived, DQ2-restricted T cells from patients. The enzyme causes deamination of gliadin peptides, and this produces negative charges that allow the peptides to bind the DQ2 molecules. It is interesting that enzymatic alteration fo food ingredients can result in termination of tolerance to autoantigens (Feltkamp et al, 1999). Rheumatoid Arthritis: Genetic factors contribute up to 60% of the susceptibility for rheumatoid arthritis. Histocompatibility leukocytes antigens (HLA) accounts for only about half of these, but the search for the genes representing the other half is hampered by the fact that familial clustering is rare, and that the onset of the disease is so late that often both parents of the patient are not alive. The gene encoding corticotrophin-releasing hormone (CRH) is a promising candidate for regulating susceptibility. CRH plays a central role in the regulation of cortisol, a key modulator of the immune response. The data from screening families with microsatellites surrounding the CRH gene, reveals a preliminary evidence for linkage 3 (Feltkamp et al, 1999). Adjuvant Arthritis: Although antigen-presenting cells and CD41 T cells are present in the lesions of adjuvant arthritis, the disease is due to adjuvant properties rather than crossreacting antigens. Microsatellite based analysis of F2 crosses between DA rats sucsceptible for oil-induced arthritis (OIA), and Lewis rats revealed non-MHC relevant loci including OIA2 on chromosome 4 and OIA3 on chromosome 10. The OIA2 locus corresponds to the candidate genes for CD4, CD120a/b and the receptor cluster for natural killer cells. The OIA3 locus corresponds to the loci for the tissue inhibitor of metalloproteinase 2 (TIMP2) and protein kinase C genes. The adjuvant effect may play a role in the initial events leading to chronic arthritis, which is followed by a specific immunity to risk target gene products (Feltkamp et al, 1999). Systemic lupus erythematosus (SLE): Activation of Receptor Editing: In patients with systemic lupus erythematosus, the use of distal Vk genes and downstream Jk genes, together with a low level of somantic mutations in Vk, suggested that B cells were undergoing secondary re-arrangements of Vk. This receptor editing was first desribed in transgenic mice as a device to delete autoantibody specificity. Further evidence of receptor editing in a wide range of B-cells in SLE patients was revealed by the fact that somatic mutations in VL were considerably less than in the partner VH. These unexpected disease specific findings suggest a hyeractive receptor-editing mechanism in SLE. This raises the question, what is driving this, and how it is related to induction of autoantibodies (Stevenson & Natvig, 1999). Conclusion This paper has highlighted autoimmune diseases, their biological basis, methods of detection and study. The genetic risk factors for autoimmune diseases which form their biological basis have been identified: they include normal B-cell behavior, autoantibody recognition sites, transforming growth factor b1 (TGF-b1) and the role of cytokines. The classification of autoimmune diseases, the methods of their detection and study have also been determined. Autoimmune diseases are those which result from an immune response from an individual’s own autochthonous antigens. It is a condition in which tissue injury is caused by T-cell or antibody reactivity to self. The effector mechanisms are the same as those associated with conventional immune responses to invading pathogens including soluble antibody, CD4 T cells, CD8 T cells, macrophages and other phagocytic cells and mast cells. The occurrence of autoimmune disease is associated with a combination of genetic predisposition, or due to environmental influences, somatic mutations and random receptor mutations. The importance of heredity in autoimmune diseases has been confirmed through studies (Rose & Mackay, 2006). B cells have to survive and flourish in a milieu of surrounding cells and their modulating receptors and factors; specific targeting of these cells for future treatment of autoimmune disease will require ingenuity, and a pooling of knowledge and resources (Stevenson & Natvig, 1999). References Davidson, A. & Diamond, B. (2001). Advances in immunology: Autoimmune disease. New England Journal of Medicine, 345: 340-350. Feltkamp, T.E.W. & Aarden, L.A., Lucas, C.J., Verweij, C.L. & de Vries, R.R.P. (1999). Genetic risk factors for autoimmune diseases. Immunology Today, 20(1): 1-3. Harold, C. (Ed.). (2008). Professional guide to diseases. The United States of America: Lippincott, Williams & Wilkins. Kuchroo, V.K., Sarvetnick, N. & Hafler, D.A. (2002). Cytokines and Autoimmune Diseases. New Jersey: Humana Press Inc. Moghaddam, P.H., Zwinderman, A.H., de Knijff, P. et al. (1997). Diabetes. Diabetes, 46: 1514- 1515. Rose, N.R. & Mackay, I.R. (2006). The autoimmune diseases. The United States of America: Academic Press. Stevenson, F.K. & Natvig, J. (1999). Autoantibodies revealed: the role of B cells in autoimmune disease. Immunology Today, 20(7): 1-3. Read More