Tolerance, Autoimmunity, Immunodeficiences

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 Tolerance

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 Vh-DJh Vl-Jl stem cellpro Bpre B D-Jh IgM immature B IgD IgM mature B Exit bone marrow Cortex Medulla 90% of thymocytes die in cortex 10% of thymocytes mature to T-cells 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 Athymic nude CD4 + CD25 - T cells Autoimmune diseases Athymic nude CD4 + CD25 - T cells + CD4 + CD25 + Treg No disease

Clonal anergy of self-reactive lymphocytes can also occur in the periphery CD28 Tissue cell has no B7 No co-stimulation Anergy Inactivation of the cell – nonresponder T cells 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, TGF  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 Genetics. Presentation of self-antigens by MHC molecules: Linkage to certain MHC alleles in many autoimmune diseases Autoreactive lymphocytes Initiating Event: Environmental: Chemical exposure Infection: Viral and bacterial infection molecular mimicry-cross reactivity between a microbial antigen with a self-antigen Gender: Females more frequently affected ‘Handedness’: a tenuous but statistically-significant higher frequency in left-handed people Contributing factors

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 thyroid- stimulating 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  -islet cells Hashimoto’s Thyroiditis - anti-thyroglobulin T/B-cells Rheumatoid Arthritis – chronically inflamed synovium activated T cells, macrophages, B cells inflammatory cytokines – TNF- , IL-1

Murine model of MS

Rheumatoid Arthritis Immunotherapy with anti-TNF  antibodies Anti-IL-1  R antagonist – to block action of IL-1 

Immunodeficiencies 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” Immunodeficiencies – when one or more component of the immune system is defective

Genetic defects may affect components of èinnate immune system – phagocytic cells, complement èadaptive 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) è 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 DeficiencyDisease___________________ B cell Recurrent bacterial infections T cellSusceptibility to viruses, fungi, protozoans T & B cellInfections with bacteria, viruses, fungi, protozoans Phagocytic cellsSystemic infections with bacteria that are of low virulence ComplementBacterial infections

Defects in the innate arm of the immune system Defective Genes/Proteins Cells AffectedDecreased resistance to Leukocyte Adhesion Molecules Enzymes involved in intracellular killing ComplementNot Applicable Phagocytes Pyogenic (pus forming) bacteria Intracellular & Extracellular microbes Pyogenic (pus forming) bacteria and Neisseria

Defects in the adaptive arm of the immune system

Generalized defects of the adaptive immune system 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

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 Measuring Immune Responses to determine immunodeficiency