Autoimmunity Immunology

Autoimmunity failure of the tolerance processes to protect the host from the action of self-reactive lymphocytes causing autoimmune diseases . result from the destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells affect between 3% and 8% of individuals in the industrialized world (rising problem) categorized as either organ-specific or systemic, depending on whether they affect a single organ or multiple systems in the body.

Autoimmune diseases are caused by immune stimulatory lymphocytes or antibodies : recognize self components, resulting in -- cellular lysis and/or an inflammatory response in the affected organ -- damaged cellular structure is replaced by connective tissue (fibrosis),-- function of the organ declines.

Immunologic Abnormalities Leading to Autoimmunity Autoimmunity results from some combination of three main immunologic aberrations. Defective tolerance or regulation: Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs Defective numbers and functions of regulatory T lymphocytes Defective apoptosis of mature self-reactive lymphocytes Inadequate function of inhibitory receptors

Abnormal display of self antigens Abnormal display of self antigens. Abnormalities may include increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury. If these changes lead to the display of antigenic epitopes that are not present normally, the immune system may not be tolerant to these epitopes, thus allowing anti-self responses to develop.

Inflammation or an initial innate immune response Inflammation or an initial innate immune response. Infections or cell injury may elicit local innate immune reactions with inflammation. These may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcomes regulatory mechanisms and results in excessive T cell activation. These may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcomes regulatory mechanisms and results in excessive T cell activation. Much recent attention has focused on the role of T cells in autoimmunity for two main reasons:

First, helper T cells are the key regulators of all immune responses to proteins, and most self antigens implicated in autoimmune diseases are proteins. Second, several autoimmune diseases are genetically linked to the MHC (the HLA complex in humans), and the function of MHC molecules is to present peptide antigens to T cells.

Environmental Factors Favoring the Development of Autoimmune Disease lifestyle factors, such as diet, suggest a link in the development of autoimmune disease. For instance, we now know that cross-talk between gut microflora and the systemic immune system may help regulate peripheral tolerance, which could impact the development of autoimmune disease. Infections may also influence the induction of autoimmunity. The molecular structures of certain microbes may share chemical features with self components, resulting in the activation of immune cells with cross-reactive potential.

The Role of Genes in Susceptibility to Autoimmunity Some studies have shown association between expressing particular MHC allele and susceptibility to autoimmunity Individuals that express HLA-B27 have 90 times greater chance of having ankylosing spondylitis (spine inflammation) Some non-MHC inherited genetic mutations mutations in immune-related gene, FoxP3 result in forms of autoimmunity inability to generate the TREG cells needed to maintain peripheral tolerance

Organ-specific autoimmune diseases Target antigen specific to organ or gland Cellular lysis and chronic inflammation that can damage organ Alternatively, anti-self antibodies may over stimulate or block the normal function of the target organ.

Hashimoto’s Thyroiditis Mainly middle-aged women autoantibodies and sensitized TH1 cells specific for thyroid antigensincluding thyroglobulin and thyroid peroxidase, which are involved in the uptake of iodine. resulting in (DTH) intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers Goiter can form Hypothyroidism

Insulin-Dependent Diabetes Mellitus Abs against beta cells that produce insulin (beta cells) The attack begins with cytotoxic T lymphocyte (CTL) infiltration and activation of macrophages followed by cytokine release and the production of autoantibodies, which leads to a cell-mediated DTH response Autoantibodies specific for beta cells may contribute to cell destruction by facilitating either antibody-mediated complement lysis or antibody-dependent cell-mediated cytotoxicity (ADCC).

In some autoimmune diseases, antibodies act as agonists Bind inappropriately to receptors, resulting in overproduction For example, up-regulating a hormonal response without the presence of that hormone Grave’s Disease – auto-Ab binds to receptor for thyroid stimulating hormone resulting in over-stimulation of thyroid Myasthenia gravis Auto-Abs bind acetylcholine receptors on motor end plate of muscles – progressively weakened skeletal muscles

Systemic Autoimmune Diseases Response is directed toward wide range of target and involves a number of organs and tissues Tissue damage is typically widespread, both from cell-mediated immune responses and from direct cellular damage caused by auto-antibodies or by accumulation of immune complexes.

Systemic Lupus Erythematosus Typically middle-aged women Fever, weakness, arthritis, skin rash, kidney problems Produce auto-Abs to DNA, histones, platelets, leukocytes, clotting factors Auto-antibodies specific for RBCs and platelets can lead to complement-mediated lysis, resulting in hemolytic anemia and thrombocytopenia, respectively.

When immune complexes deposited along the walls of small blood vessels, a type III hypersensitivity reaction develops. The complexes activate the complement system and generate membrane-attack complexes and complement fragments (C3a and C5a) that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis. Laboratory diagnosis of SLE involves detection of antinuclear antibodies directed against double-stranded or single stranded DNA, nucleoprotein, histones, and nucleolar RNA. Indirect immunofluorescent staining with serum from SLE patients produces characteristic nuclear-staining patterns

Multiple sclerosis Numbness, paralysis, vision loss Individuals with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers in the brain and spinal cord. A breakdown in the myelin sheath leads to numerous neurologic dysfunctions Infection by certain viruses, such as Epstein-Barr virus (EBV), may predispose a person to MS.

Rheumatoid Arthritis Chronic inflammation of joints Produce auto-Abs (called rheumatoid factors) that bind Fc portion of IgG circulating in blood that creates immune complexes The classic rheumatoid factor is an IgM antibody that binds to normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints. can activate the complement cascade, resulting in a type III hypersensitivity reaction, which leads to chronic inflammation of the joints.

Treatment Immunosuppressive drugs Removal of thymus (for example, with myasthenia gravis) Plasmapheresis – removing plasma and then returning RBCs (removes extra immune complexes) Treating the inflammation Antigen given orally can induce tolerance

Refferences : Immunology , Kuby, seventh edition 2013 Immunology , Kuby, eighth edition 2019 Medical microbiology, Jawetz, 26th edition Cellular and Molecular Immunology, Abul K. Abbas, 8th edition.