Immunology VI. AUTOIMMUNITY

AUTOIMMUNITY is an immune response that is directed against self-antigen(s);

Autoimmune Diseases are conditions where the autoimmune response is responsible for the tissue or organ damage.

A. Mechanisms of breakdown in tolerance. Autoimmunity requires a breakdown in the mechanism of self-tolerance. During the development of the lymphocyte repertoire in the bone marrow and thymus, T and B cells with self-reactive receptors are eliminated or rendered anergic (unresponsive) to prevent immune system self-reactivity. Additional mechanisms of peripheral tolerance are also involved in controlling self-reactive lymphocytes.
1. Genetic factors. Autoimmune diseases tend to run in families. The genetic contribution to autoimmune diseases often involves multiple genes; however, there are some genetic components that are associated with increased risk for the development of certain autoimmune disorders.
Many of the strongest and best characterized genetic associations with autoimmune disorders involve different variants of MHC/HLA: HLA-B27 and increased risk of ankylosing spondylitis, HLA-DR3 or -DR4 and increased risk of insulin-dependent diabetes mellitus (IDDM), HLA-DR4 or -DR1 and increased risk of rheumatoid arthritis, and HLA-DR2 and a protective effect for the development of IDDM.

2. Hormonal influences. There is a general trend for autoimmune disease to occur more frequently in women than in men, probably due to differences in hormone profiles. The precise mechanism is unknown.

3. Infection. Molecular mimicry, or shared/similar epitopes in pathogen antigens and self-antigens, can elicit autoimmune disorders (e.g., immune reactivity to group A streptococcal M proteins and the development of rheumatic fever). Additionally, infection in a target organ induces the expression of co-stimulatory molecules and the presentation of pathogen and self-antigens through the action of IFN-g.

B. Organ-specific autoimmune disorders usually affect a single organ, most often an endocrine gland.
1. Hashimoto thyroiditis involves the infiltration of mononuclear cells, including lymphocytes, macrophages, and plasma cells, into the thyroid, resulting in destruction of follicular cells and a general breakdown in the architecture of the thyroid. The immune mechanisms involve antibody and cell mediated components. The resulting hypothyroidism is treated with synthetic thyroid hormone replacement (levothyroxine sodium also known as Synthroid, Levoxyl, Levothroid, or Unithroid).

2. Graves disease is the result of antibodies that act as agonists of thyroid-stimulating hormone (TSH) by binding to the TSH receptor and stimulating the release of thyroid hormones. The resulting hyperthyroidism is treated by antithyroid drugs (e.g., propylthiouracil or methimazole) or thyroid ablation by radiation or surgical removal, which would then be treated with synthetic thyroid hormone replacement therapy.

3. Rheumatic fever is due to the production of antibodies directed against the M proteins of group A streptococci (GAS), which are cross-reactive to antigens present in the heart. Early identification and antimicrobial treatment during an infection with GAS is important to prevent the formation of the antibodies. Repeated streptococcal infections can lead to further damage to the heart tissue (rheumatic heart disease).

4. Autoimmune-hemolytic anemia (erythrocyte), -thrombocytopenia (platelet), -neutropenia (neutrophil), and -lymphopenia (lymphocyte) are mediated by antibodies directed against antigens intrinsic to the cell surface of the affected blood cell. It is important to discriminate between type II hypersensitivity-mediated cellular destruction, which is often due to the transient presence of extrinsic antigens on the surface of the cell, and autoimmune disease, which would be due to immune activity toward self-antigens. Autoimmune responses may need immunosuppressant therapy to halt the destruction, whereas hypersensitivity is often self-limiting and resolves when the extrinsic antigen is no longer present. For autoimmune hemolytic anemia, transfusions may be required. Plasmaphoresis to remove self-reactive antibodies or splenectomy can slow the erythrocyte destruction in severe cases.

5. With myasthenia gravis, antibodies are directed against the acetylcholine receptor (Ach-R) on the motor end plates of the muscle cells, blocking the binding of acetylcholine and mediating complement-dependent damage to the receptor and cell membrane. The patient experiences variable skeletal muscle weakness, often appearing first as drooping eyelids, double vision due to an impairment of extraocular eye muscles. Acetylcholinesterase inhibitors, neostigmine (Prostigmin), pyridostigmine (Mestinon and Regonol), and others are the first line of treatment, followed by corticosteroids for long-term control, or other immunosuppressants (e.g.,  cyclosporine or azathioprine) for more severe cases.

6. Insulin-dependent diabetes mellitus (IDDM or type I diabetes) is caused by the selective destruction of the islets of Langerhans of the pancreas. Destruction involves T cells and often antibodies directed against antigens in the pancreatic b-cell, the primary producer of insulin. Disease symptoms appear when the destruction is nearly complete and the insulin levels are low. Increased risk of developing IDDM is associated with HLA-DR3 and -DR4. Current therapy targets the replacement of the insulin. Immunotherapeutic approaches to consistently and safely prevent or reverse IDDM have not been developed in humans.

7. Goodpasture syndrome is characterized by progressive glomerulonephritis and frequently, pulmonary hemorrhage (particularly in those who smoke). The tissue damage is due to the production of antibodies directed against antigens of type IV collagen, which is present in the basement membrane in the lungs and glomeruli. The risk of developing Goodpasture’s is strongly associated with certain variants of HLA-DRB1. Patients are treated by plasmaphoresis, followed by systemic corticosteroids, and often cyclophosphamide.

 8. Multiple sclerosis (MS) is an inflammatory, demyelinating neurodegenerative, autoimmune disease of the central nervous system. The exact immune mechanism is not completely understood; however, TH1 cells and the inflammatory cytokines that they secrete (e.g., IFN-g) are strongly implicated. The clinical features, which include sensory disturbance and motor dysfunction, can be highly variable and dependent on many factors, such as the sites of pathological lesions and the rate of new lesion formation. Treatment strategies focus on reducing the inflammation within the CNS, and include interferon b-1b (Betaseron and Extavia), interferon b-1a (Avonex and Rebif), glatiramer acetate, mitoxantrone, fingolimod, and natalizumab.

C. Non-organ specific or systemic autoimmune diseases affect multiple organs, usually associated with antigens found throughout the body.

1. Sjögren syndrome (SjS) is a complex, chronic autoimmune disease, which is characterized by mononuclear cell infiltration of exocrine glands resulting in reduced or loss of secretory function. SjS may present as either primary SjS or as secondary, occurring in association with other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, or other connective tissue disorders. The precise immune mechanism is not completely understood. Mild cases are treated with artificial tears, medications for dry eyes (cyclosporine ophthalmic emulsion and hydroxypropyl cellulose ophthalmic inserts), medications for dry mouth (cevimeline, and pilocarpine hydrochloride), and frequent drinking of water. Systemic manifestations often require immunosuppressive therapy, such as systemic corticosteroids, to treat internal organ manifestations or severe flares.

 2. Rheumatoid arthritis (RA) is a chronic, recurrent, systemic inflammatory disease that principally involves the joints. It is characterized by the presence of rheumatoid factors (autoantibodies directed against the Fc portion of IgG) in the serum and synovium, infiltration of lymphocytes and activated macrophages into involved joint synovium, and local production of TNF-a and other proinflammatory cytokines in involved synovium. Therapy is generally aimed at reducing synovial inflammation in order to improve symptoms and preserve joint function. Specific therapeutic interventions are required.

3. Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder directed to self-antigens that are present in all or nearly all cells of the body, most typically nuclear components, such as nucleic acids and nucleoprotein particles. The immune complex formation initiates inflammatory reactions leading to cell and tissue destruction. Symptoms are variable depending on the site of immune complex formation and may be intermittent, which complicates diagnosis. 

Joint pain and swelling are the most common symptoms. Other symptoms include fatigue, fever with no other cause, malaise, hair loss, mouth sores, skin rashes (described as a butterfly rash on the face in some patients), sensitivity to sunlight, and swollen lymph nodes. For individual patients, the course of the disease is highly variable in terms of severity, the organs and tissues involved, and the progression of the disease. Mild disease may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroid creams for the skin rashes. Hydroxychloroquine (Plaquenil, an antimalarial medication) is sometimes useful in patients whose symptoms have not improved with other interventions. Belimumab (Benlysta), a monoclonal antibody inhibitor of B cells, is a newly FDA-approved drug for use in SLE.  

More severe cases of SLE are often treated with high-dose corticosteroids or cytotoxic drugs (e.g., cyclophosphamide). When flares have subsided, the dose can often be lessened to reduce side effects.  

Drug-induced lupus erythematosus is similar to SLE in terms of the clinical presentation; however, it is caused by a hypersensitivity reaction to a medication (e.g., chlorpromazine, hydralazine, isoniazid, methyldopa, penicillamine, procainamide, quinidine, and sulfasalazine). Symptoms tend to occur after taking the drugs for at least 3 to 6 months, and they tend to resolve when the medication is discontinued.

Ref:
Comprehensive Pharmacy Review 

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