Chapter 16 Tolerance and Autoimmunity Dr. Capers

Kuby IMMUNOLOGY Sixth Edition Chapter 16 Tolerance and Autoimmunity Copyright © 2007 by W. H. Freeman and Company Kindt Goldsby Osborne

“Horror Autotoxicus”  Failure of host’s humoral and cellular immune systems to distinguish self from non-self Autoimmunity Can result in tissue and organ damage, can be fatal

Tolerance  # of mechanisms are in place to protect individual from self-reactive lymphocytes Central tolerance – deleting T or B clones before maturity if they have receptors that recognize self-antigens with great affinity Peripheral tolerance – kills lymphocytes in secondary lymphoid tissue ○ Also, life span of lymphocytes regulated by apoptosis

 Some antigens can produce tolerance Termed tolerogens rather than immunogens ○ High dosages of antigen ○ Persistance of antigen in host ○ IV or oral introduction ○ Absence of adjuvants ○ Low levels of costimulators CD28 will bind to B7 and provide activating signals; however, it was discovered that another receptor, CTLA-4 will bind to B7 and inhibit

 Anergy Unresponsiveness to antigenic stimulus

The F1 mouse does not have any B cells that Express anti-HEL antibodies

 Peripheral Tolerance May be induced by T reg cells ○ Unique group of CD4+ T cells ○ Recognize self- antigens on immune system cells and seem to be able to suppress immune system ○ Induce cell death in some immune cells

Organ-specific autoimmune diseases  Target antigen specific to organ or gland  Cellular lysis and chronic inflammation that can damage organ

 Hashimoto’s Thyroiditis Mainly middle-aged women Target is thyroid antigens Goiter can form Hypothyroidism - decrease

 Autoimmune anemias Pernicious anemia ○ Ab against membrane bound intestinal protein that uptakes B 12 - needed for hematopoiesis Hemolytic anemia ○ Abs to red-blood cell antigens Drug-induced anemia

 Goodpasture’s syndrome Abs against basement membranes in glomeruli and aveoli Leads to kidney damage and pulmonary hemmorhage

 Insulin-Dependent Diabetes Mellitus Abs against beta cells that produce insulin Insulin is needed by cells to uptake glucose needed for cellular respiration

 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 antigens

 Systemic Lupus Erythematosus Typically middle-aged women Fever, weakness, arthritis, skin rash, kidney problems Produce auto-Abs to DNA, histones, platelets, leukocytes, clotting factors Excessive complement activation

 Multiple sclerosis Numbness, paralysis, vision loss Inflammatory lesions in myelin sheath caused by T cells Epidemiology ○ Frequent in African American and Hispanic women ○ More common in Northern Hemisphere, more common north of 37 th parallel ○ Environmental components as well as genetic components

 Rheumatoid Arthritis Chronic inflammation of joints Produce auto-Abs that bind Fc portion of IgG circulating in blood that creates immune complexes

Animal Models  Autoimmunity develops spontaneously in some lab animals and can be induced with manipulation Rabbits injected with acetylcholine receptors from eels ○ Soon developed muscular weakness as seen with Myasthenia gravis

 Animal models have implicated CD4+ T cells to be primary mediator of some autoimmune responses Treatment with anti-CD4 antibodies can help

 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) ○ Interestingly, most of those are male even though women are more likely to suffer from autoimmune disease

 Proposed mechanisms for induction of autoimmunity Release of sequestered antigens ○ Blood-brain barrier, sperm released into tissues during vasectomy Molecular mimicry Inappropriate expression of Class II MHC ○ Non-antigen presenting cells will for some reason express Class II MHC -Can be caused by viral infection ○ This allows them to present self antigen to T helper cells – leads to inappropriate reaction

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