Autoimmune Diseases and Mechanism of Autoimmunity Mrs P

Autoimmune Diseases and Mechanism of Autoimmunity Mrs. P. Kalpana Lecturer in Biotechnology Govt. College for Men (A), Kadapa, A. P.

Overview • Introduction to immune response • Tolerance • Autoimmunity (self – nonself) • Types • Possible mechanisms / Factors • Diseases – Diagnosis • Treatment strategies

Immune System • Living organisms provide ideal habitat in which other organisms can grow • Organisms have evolved a complicated, dynamic network of cells, molecules and pathways – Immune system

Immune System Source: https: //www. aids. gov

Immune System • Pathogens evolve countermechanisms to avoid immune destruction • Infections –the immune system is not always successful • Immune response – distinguish between self and non-self

Tolerance • Protection by the immune system to prevent the immune response against the host components • Central tolerance and peripheral tolerance

Tolerance • How does the immune system know self and non-self/foreign? • Clonal selection theory • Positive selection – cells respond to self MHC – clonal expansion • Negative selection – cells which do not bear receptors against self antigens (self tolerance)

Tolerance Source: Figure 16 -1, © 1992, 1994, 1997, 2000, 2003, 2007, 2013 by W. H. Freeman and Company ISBN 13: 978 -14641 -3784 -6

Self – non self • Production of regulatory cells • With the help of education at primary lymphoid organs self antigens and foreign (non-self) antigens can be identified • Establishment of self tolerance

Immune system – Elimination of the pathogens Source: Figure 17. 2, © 2010 John Wiley & Sons, Inc. ISBN-13 978 -0 -470 -48337 -4

Autoimunity • Sometimes immune system go wrong • Failure of immune system to distinguish self – nonself • Destructs self cells and organs Autoimmunity

Autoimmune diseases • Affect 3% - 8% of the individuals in industrialized world Based on number of organs affected 1. Organ specific or localized 2. Systemic

Organ specific or localized • The immune response is directed towards antigens specific for a particular organ Ex: Hashimoto’s Thyroiditis Type I Diabetes Mellitus

Systemic autoimmune diseases • The immune response is directed towards multiple organs or glands Ex: Rheumatoid arthritis Systemic Lupus Erythematosus Multiple Sclerosis

Mechanisms of initiation of Autoimmune disease • Autoimmunity results from failure or breakdown of self tolerance • Genetic factors • Environmental factors • Female Vs Male

Failure of B - cell tolerance Polyclonal B – cell activators • Epstein barr Virus and Cytomegalo Virus • Bacterial antigens such as LPS

Molecular Mimicry • Immune response specific for microbial antigen cross-reacts with self antigen • Conserved sequences • Unintentional autoimmune response Ex: Rheumatic fever

Molecular Mimicry Carbohydrate antigen Streptococcus To control the infection Antibodies produced against the bacterium Cross reaction with host antigens

Availability of sequestered self-antigens • Tolerance is induced in early stages of development • Sequestered or hidden antigens • Release due to injury, trauma or any other reason Ex: sperm antigens, lens of eye, heart muscle etc.

Genetic Factors • Aberrant expression of MHC - II molecules • MHC – I expression – all nucleated cells • MHC – II expression – only on Immune cells • T – cells recognize the antigen only in combination with MHC

Genetic Factors

Genetic Factors • If the MHC are expressed mistakenly on non-immune cells, they may present self antigens to Tcells • Activation of B – cells, Tcyt cells etc. • Leads to autoimmunity

Male Vs Female • Increased frequency with age • More frequent in women than men – Female predominance • Autosomes + XX - Female • Autosomes + XY - Male

Male Vs Female Disease Female to male ratio Hashimoto’s Thyroiditis 50 : 1 SLE 9: 1 Grave’s disease/Hyperthyroidism 7 : 1 Rheumatoid arthritis 3: 1 Multiple sclerosis 2: 1

Male Vs Female - Reasons • Reasons are not entirely understood • Significance gender differences in immune responses • Females mount more vigorous immune response • Hormone differences with respect to autoimmunity (Estrogen Vs Androgen) Ex: SLE Pregnancy +, Menopause -

X-chromosome inactivation • Women have two ‘X’ chromosomes but men have only one ‘X’ chromosome • X-chromosome has thousands of genes essential for cell activity • Women may have double dose of the X –chromosome encoded gene products

X-chromosome inactivation • Actually, women also have same amount of gene products as men – Dosage compensation. • Presence of only one functional Xchromosome in somatic cells • Mary Lyon - 1961

Lyon Hypothesis • Both X chromosomes were active at very early development • As development proceeds one chromosome is turned off • This inactivation is random and irreversible

Multifactorial and polygenic • Autoimmunity does not develop from a single event Initial trigger Formation of auto-reactive T cells Negative selection Failure of Negative selection (under spl. circumstances) Autoimmunity

Clinical associations among autoimmune diseases • More than one autoimmune disease • Autoimmune thyroiditis – gastric parietal cells – adrenal cortex

Rheumatoid arthritis (RA) • Systemic autoimmune disease • Cardiovascular, hematological and respiratory systems are affected • Chronic inflammation of the joints • Female to male ratio is 3: 1 • Diagnosis - Presence of RF antibody, anti-CCP antibodies

Rheumatoid arthritis (RA) Source: http: //www. aihw. gov. au/rheumatoid-arthritis/about/

Systemic Lupus Erythematosus (SLE) • Systemic autoimmune disease • Antibodies against many self antigens • Skin, joints, kidneys, brain and other organs • Female to male ratio is 9: 1 • Presence of Anti nuclear antibodies • Butterfly rash on face

Systemic Lupus Erythematosus (SLE) Source: Page 708, © 2010 John Wiley & Sons, Inc. ISBN-13 978 -0 -470 -48337 -4

Type I Diabetes Mellitus • Organ specific autoimmune disease • Juvenile onset diabetes or Insulin Dependent Diabetes Mellitus (IDDM) • β - cells of the Pancreas • 2 in 1000 children • Autoimmune attack by T-cells • Female to male ratio is 1: 1 or 2: 1

Type I Diabetes mellitus • Hyperglycemia, Ketoacidosis and increased production of Urine • Administration of insulin daily • Undetected for many years – irreparable loss of pancreatic tissue

Grave’s disease • Thyroid gland • Immune attack on TSH receptors • Auto-antibodies bind to TSH receptor • Leads to prolonged stimulation of thyroid cells – Hyperthyroidism • Female to male ratio is 7: 1

Grave’s disease Source: Figure 20 -4, Immunology, 5 th edition, ISBN-13: 978 -0716749479 © 1992, 1994, 1997, 2000, 2003, 2007, 2013 by W. H. Freeman and Company

Hashimoto’s thyroiditis • Immune attack against one or more common proteins of thyroid cells • The resulting destruction of the thyroid gland leads to hypothyroidism • Female to male ratio is 50 : 1

Animal Models • Animal models help in understanding the autoimmunity in humans • Certain autoimmune diseases develop spontaneously in animals • Some of them are induced by certain experimental manipulations

Animal Models • Non obese diabetic mouse –IDDM • (NZB x NZW) F 1 mouse – SLE • Obese strain Chicken–Hashimoto’s • Experimental Autoimmune Encephamyelitis –MS • Autoimmune Arthritis - RA

Treatment • Treatment is aimed at reducing only the autoimmune response • Current therapies – no cure • Reduce the symptoms – to provide acceptable quality of life • Nonspecific suppression of immune system

Treatment • Cannot distinguish the pathological immune response and protective immune response • Immune suppression – increased risk of infections, developing cancer

Treatment • Animal models – Vaccination with T-cell specific for autoantigen • Peptide blockers – competitors of autoantigen • Treatment with monoclonal antibodies • Induction of tolerance – by oral/ mucosal administration of autoantigen

Summary • Introduction to immune response • Tolerance • Autoimmunity (self – nonself) • Types • Possible mechanisms / Factors • Diseases – Diagnosis • Treatment strategies

Reference Books • Kuby Immunology, 7 th Edition, Judith A. Owen, Jenni Punt, Sharon A. Stranford and Patricia P. Jones. • Immunology, 5 th Edition, Richard A. Goldsby, Thomas J. Kindt, Janis Kuby, Barbara A. Osborne. • Cell and Molecular biology, 6 th Edition, Gerald Karp. • Roitt’s Essential Immunology, 10 th Edition, Ivan M. Roitt & Peter J. Delves.