Transcript Document
Tolerance, Autoimmunity, Immunodeficiences Tolerance Tolerance is broadly defined as a state of unresponsiveness to an antigen, be it self or foreign Antigen-specific cell receives signals that either activate OR inactivate the cell Central tolerance to self antigens is acquired during development through the elimination or silencing of lymphocytes capable of binding self antigens Peripheral tolerance is induced in mature lymphocytes in the periphery Mechanisms to induce tolerance Elimination of self-reactive lymphocytes = clonal deletion (negative selective of T and B cells during development) Silencing of self-reactive lymphocytes = clonal anergy Clonal deletion of self-reactive lymphocytes occurs within primary lymphoid organs stem cell pro B D-Jh Vh-DJh pre B immature B Vl-Jl IgM Cortex 90% of thymocytes die in cortex Medulla IgM Exit bone marrow mature B 10% of thymocytes mature to T-cells IgD B-cells – bone marrow T-cells - thymus Clonal deletion can also occur in the periphery Mechanisms • Fas – FasL interactions: apoptosis • T suppressor/regulatory cells – Treg, CD4+CD25+ may kill by perforin/granzyme mechanism Autoimmune diseases CD4+CD25- T cells Athymic nude No disease CD4+CD25- T cells + CD4+CD25+ Treg Athymic nude Clonal anergy of self-reactive lymphocytes can also occur in the periphery T cells Tissue cell has no B7 No co-stimulation CD28 Anergy Inactivation of the cell – nonresponder B cells – can also be anergized in the absence of co-stimulation, usually CD40-CD40L Other factors involved in Tolerance -Dose/Route of Antigen -Inappropriate cytokine responses -anti-idiotypic responses -Psychogenic factors (poorly defined but could include the immunosuppressive effect of steroid hormones) Tolerance to a fetus The fetus is really an allograft with nonself MHC proteins & RBCs of the father so why is it not rejected by the mother? We know mothers’ makes antibodies against fathers’ MHC & RBC Potential mechanisms Placenta – outer layer does not express classical MHC proteins expresses a molecule that inhibits NK cell killing depletion of tryptophan – necessary T cell nutrient T cell tolerance to paternal ags, suppressed T cell responses Secretion of cytokines that suppress TH1 cells – IL4, IL10, TGFb Role for Treg cells? “Immune privileged” sites Eye Testis Brain Ovary Placenta Potential reasons The presence of FasL expressing cells that kill infiltrating inflammatory T cells (Fas) Immunosuppressive cytokines Autoimmunity Autoimmunity constitutes immune response against self antigen. Autoimmunity may be benign or may be damaging to host An immune response against self antigen(s) that results in the destruction of host tissue or damage to the function of an organ or tissue constitutes autoimmune disease Autoimmunity can be thought of as a breakdown of tolerance, which is multi-layered, consisting of both central and peripheral mechanisms Occasionally, self-reactive cells escape, resulting in autoimmune diseases (approximately 5% U.S. population) Autoimmune diseases are multifactorial – genetic & environment Contributing factors • Genetics. Presentation of self-antigens by MHC molecules: Linkage to certain MHC alleles in many autoimmune diseases •Initiating Event: Environmental: Chemical exposure Infection: Viral and bacterial infection molecular mimicry-cross reactivity between a microbial antigen with a self-antigen •Autoreactive lymphocytes •Gender: Females more frequently affected •‘Handedness’: a tenuous but statistically-significant higher frequency in left-handed people Bacterial infections can lead to immune-mediated pathology Classification of autoimmune disease Historically – organ or systemic Effector mechanism – antibody, complement, T cells Antibody mediated diseases Autoimmune hemolytic anemia – destruction of RBCs Myasthenia Gravis – autoab to acetylcholine receptor, inhibits nerve impulse transmission (blocking ab) Graves disease – autoab to receptor for thyroidstimulating hormone, activates cell to release thyroid hormone (activating ab) Systemic Lupus Erythematosus - wide spectrum of autoreactive antibodies, anti-nuclear antibodies against DNA,RNA, or nucleoproteins Systemic Lupus Erythematosus Characteristic butterfly rash Damage to several organs Kidney – immune complex deposition can lead to activation of C, inflammation Kidney damage causes the most mortality in SLE Trigger unknown T cell mediated diseases Multiple Sclerosis – demyelinization of CNS tissue T cell response to myelin Type 1 Insulin-Dependent Diabetes Mellitus – Cytotoxic T cells to pancreatic b-islet cells Hashimoto’s Thyroiditis - anti-thyroglobulin T/B-cells Rheumatoid Arthritis – chronically inflamed synovium activated T cells, macrophages, B cells inflammatory cytokines – TNF-a, IL-1 Murine model of MS Rheumatoid Arthritis Immunotherapy with anti-TNF a antibodies Anti-IL-1bR antagonist – to block action of IL-1b Immunodeficiencies Immunodeficiencies – when one or more component of the immune system is defective • Inherited immunodeficiences (genetic) are the most common IgA deficiency the most common of these (1 in 800) The rest are rare (1 in 10,000) • Acquired immunodeficiency - caused by malnutrition, seen in infants and children - caused by drugs or irradiation - caused by viral infection, seen in patients of all ages - alcoholism • age – very young or very old are “immunodeficient” Genetic defects may affect components of innate immune system – phagocytic cells, complement adaptive immune system – T cells, B cells defects that affect CD4 T cells or the developmental stages of T and B cells severely compromise immune function. These are referred to as Severe Combined Immunodeficiency Disease (SCID) both innate and adaptive immune systems multiple defects that affect both arms of the immune system also result in severe compromise of immune functions. These are rare. Immunodeficiency Is often recognized by recurrent infections The type of infection depends on which component of the immune system is compromised Deficiency B cell T cell T & B cell Phagocytic cells Complement Disease___________________ Recurrent bacterial infections Susceptibility to viruses, fungi, protozoans Infections with bacteria, viruses, fungi, protozoans Systemic infections with bacteria that are of low virulence Bacterial infections Defects in the innate arm of the immune system Defective Genes/Proteins Leukocyte Adhesion Molecules Enzymes involved in intracellular killing Complement Cells Affected Decreased resistance to Phagocytes Pyogenic (pus forming) bacteria Phagocytes Intracellular & Extracellular microbes Not Applicable Pyogenic (pus forming) bacteria and Neisseria Defects in the adaptive arm of the immune system Defective genes/proteins Cell type affected phenotype Susceptibility to Bruton’s tyrosine kinase B cells Agammaglobulinemia Extracellular bacteria CD40 ligand T cells No antibody responses, no isotype switching Extracellular bacteria B cells No IgA or IgG antibodies Respiratory infections Nucleated cells No CD8 T cells viral infections APC No CD4 T cells, generalized (x-linked) (x-linked) IgA deficiency, CVID (IgG and IgA def) Expression of MHC class I Expression of MHC class II SCID Generalized defects of the adaptive immune system Defective gene/protein Cell type affected phenotype susceptibility DiGeorge Syndrome (Athymic) T-cells SCID general Purine degradation enzymes Developing SCID general Recombinases, DNA repair enzymes Developing SCID general SCID general chain of cytokine receptors T cells B and T cells T and B cells (x-linked) Note: chain is shared by receptors for IL2, IL4, IL7, IL9 and IL15 Acquired Immunodeficiencies Severe immunodeficiency caused by HIV (AIDS) generalized immunosuppression due to loss of CD4 T cells. Immune suppression induced by Epstein-Barr Virus (EBV) following infectious mononucleosis. Radiation or Cytotoxic drugs Malnutrition Alcoholism Measuring Immune Responses to determine immunodeficiency •Innate Immunity: ELISA for complement components, Cytotoxicity/Phagocytosis assays •Humoral Immunity: ELISA for antibody (total and specific) enumerate B-cells proliferative capacity •Cellular Immunity: Th- skin testing (DTH or Mantoux test), proliferation, cytokine production by ELISA, enumerate CD4+ T-cells Tc- Cytotoxicity testing, IFN- production, enumerate CD8+ T-cells