Central University of South Bihar Panchanpur, Gaya, India

E-Learning Resources

Department of Biotechnology

NB: These materials are taken/borrowed/modified/compiled from various sources like research articles and freely available internet websites, and are meant to be used solely for the teaching purpose in a public university, and for serving the needs of specified educational programmes. Semester-2

BIOLOGY OF (BIS) (MSBTN2004C04, 4 credits) E-Lecture-1

Rizwanul Haque, Ph.D., Professor Department of Biotechnology, CUSB Overview of this lecture

• General introduction • Types of autoimmune diseases • Organ versus systemic • Effect, cause and mechanism of autoimmunity • Some common autoimmune diseases • Treatment option for autoimmune diseases • Possible target for future drug in autoimmune diseases What is autoimmunity? • Autoimmunity is a problem of self/non-self discrimination.

• Failure of tolerance leads to autoimmunity

 Damage can be - mediated and/or T-cell mediated  Systemic vs. organ-specific  Females > males  Tendency sometimes runs in families • In general, there is know known causes of autoimmune diseases. In most cases, your disease may have been caused by:  Genes, which may make you more likely to have the disease.  Environment, such as a that triggers the disease if you have the gene(s).  Immune system, Inappropriate regulation of gene involved in identification and neutralization foreign particles. • 5 % to 7% adult affected. • Two third women. • These diseases can affect almost any part of the body. • More than 80 human diseases autoimmune in origin. Prevalence of autoimmune diseases • Thyroid diseases (includes Hashimoto’s thyroiditis and Graves’ disease): more than 3% of adult women • : 1% of general population, but female excess • Primary Sjogren’s syndrome: 0.6% to 3% of adult women • Systemic erythematosus: 0.12% of general population, but female excess • : 0.1% of general population, but female excess • Type 1 mellitus: 0.1% of children • Primary biliary cirrhosis: 0.05% to 0.1% of middle-aged and elderly women • : 0.01% of general population, but female excess

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Ch. 16 Causes of autoimmunity Effect of Autoimmunity

1) Tissue destruction 1) Release of sequestered Ag Diabetes: CTLs destroy insulin-producing • Smoking can trigger Goodpasture’s beta-cells in pancreas syndrome 2) block normal function • Alveolar basement membrane normally not Myasthenia gravis: Ab binds exposed to immune system acetylcholine receptors • Smoking damages alveoli, exposes collagen • Anti-collagen Ag damages lung and kidney 3) Antibodies stimulate inappropriate • Anti-sperm Ab produced in some men after function vasectomy Graves’ disease: Ab binds TSH • Injection of myelin basic protein (MBP) Mimics thyroid-stimulating hormone produces MS-like EAE in mice Activates unregulated thyroid hormone • May be triggered by injury or infection production

2) Immune stimulation 4) Antigen-antibody complexes affect • Microbial infection stimulates APCs function carrying self Ag Rheumatoid arthritis: • High level of APCs with “second signal” IgM specific for Fc portion of IgG breaks anergy IgM-IgG complexes deposited in joints inflammation Mechanisms of autoimmune damage Circulating autoantibodies • Complement lysis (as in hemolytic diseases) • Interaction with cell receptors (as in myasthenia gravis, thyrotoxicosis) • Toxic immune complexes (as in systemic lupus erythematosus) • Antibody-dependent cellular (possibly in organ-specific autoimmune diseases) T lymphocytes • CD4 cells polarized toward TH1 responses by cytokines (as in rheumatoid arthritis, multiple sclerosis, ) • CD8 cells activated to become cytotoxic T cells and cause direct cytolysis Nonspecific • Recruitment of inflammatory leukocytes into autoimmune legions (as in synovitis) Ag released from hidden location Many self Ag are found in hidden location eg. C N S ,TESTES ,EYE (CORNEA)

organ damage  Lens and uveal tract of the eye. The antigens cause Hidden Ag released post-traumatic uveitis, endophthalmitis.  Spermatozoa- Reaches blood stream Aspermatogenesis (Sterility).  Central nervous system- Encounter Ag sensitive cells Encephalitis.

Stimulate autoimmunity Molecular mimicry  Rheumatic . M protein of • Sharing of epitopes Streptococcus pyogenes and glycoproteins of heart. Antibodies against M proteins between an infectious cross-react with glycoproteins of heart, agent and its host. joints and other tissues leading to rheumatic heart disease.  Type I insulin-dependent diabetes mellitus due to cross-reactions between certain B4 and islet cell antigen • Antibodies directed glutamic acid decarboxylase. , measles, rubella, and against the infectious infections mononucleosis have been implicated. agents starts reacting with  Haemolytic anaemia following normal self Ag. Mycoplasma pneumoniae infection.  Reiter syndrome occurs following Shigella, Salmonella, Yersinia, Campylobacter or Chlamydia infection.  Guillain-Barre syndrome following viral or • Triggers autoimmunity. Campylo-bacter infections.  Multiple sclerosis following viral infection.

Antibodies to receptors

Grave’s disease

Autoantibody mimics TSH, leads to constant thyroid stimulation

Myasthenia gravis

Autoantibody blocks ACh receptor, eventually destroys it

Rheumatoid Arthritis • Auto-immune disorder which results in inflammation of the synovial lining of the joint and cartilage destruction. • This result in loss of function. • Affects 1% of adults.

Autoimmunity might arise entirely from within, by an intracellular self-molecule becoming in some way aberrantly expressed at the cell surface.

Cells reactive with self antigens not present in sufficient amounts can develop, escape censorship, and migrate to the periphery.

As a result, lymphocytes from normal individuals can be activated in vitro against a variety of self antigens. However, they remain silent in vivo, causing no damage.

Factors that maintain this tolerance include low-level expression of MHC molecules

Absence of costimulatory molecules on most non-lymphoid tissue cells, insufficient expression of target autoantigens,

Low precursor frequency of autoreactive cells and low affinity of their immunoreceptors, and restricted pathways of lymphocyte homing.

If one of these factors is overcome, an autoimmune disease may develop.

The mechanisms responsible for activation of sufficient numbers of self-reactive lymphocytes and for induction of clinical symptoms remain the focus of investigation. Treatment for autoimmunity

• Immunosuppression (e.g., prednisone, cyclosporin A) • Removal of thymus (some MG patients) • Plasmapheresis (remove Ab-Ag complexes) • T-cell vaccination (activate suppressing T cells??) • Block MHC with similar peptide • anti-CD4 monoclonal Ab • anti-IL2R monoclonal Ab Selective immunotherapies for autoimmune diseases

Monoclonal antibodies or blocking antagonists • Against T-cell synapse (used for multiple sclerosis) • Against cytokines such as tumor necrosis factor (used for rheumatoid arthritis) • Against receptor for cytokines such as tumor necrosis factor (used for rheumatoid arthritis) • Against receptors for chemokines CCR5 and CXCR3 (under development) CTLA-4 • Downregulates activated T cells (trial use for psoriasis) Regulatory cytokines • Interferon beta possibly inhibits interleukin 12 (used for multiple sclerosis • Interleukins 10 and 4 divert TH1 response to TH2 response (used in animal models) Restoration of tolerance • Antigen-specific desensitization (used for multiple sclerosis, type 1 diabetes) • Stem cell replacement (used for various diseases) • Gene therapy (under development) Treatment of autoimmune disease (cont’d)

Reduce inflammation TNF-alpha blockers (RA, Crohn’s dis., psoriasis) e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, MS)

Rituxin = monoclonal Ab = anti-CD20 Eliminates B cells in non-Hodgkins lymphoma (maybe also RA, and other Ab-mediated autoimmune diseases) Possible experimental approach to overcome the autoimmune diseases Thank you