Tolerance Our own bodies produce some 100,000 different proteins and one of the longstanding conundrums of immunology has been to understand how the immune system produces a virtual repertoire against pathogens while at the same time avoiding reacting to self. The strict definition of immunological tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge with a specific antigen.
Tolerance Definition: Immunological non-reactivity to an antigen. Resulting from a previous exposure. The most important form is non-reactivity to self Ag When an antigen induces tolerance, it is tolerogen.
Tolerance Immune response TolerancePhysical form of Ag Large,aggregated, complex Soluble, smaller, less complexRoute of Ag SC or IM Oral or IVDose of Ag Optimal dose Very large (sometimes very small)Age of responding Older and immunologically Newborn, immunologicall animal mature immatureDifferentiation state Fully differentiated; memory Relatively undifferen: B, T cells of cells T and B
Tolerance, mechanism B cell tolerance • Deletion • Anergy • receptor editing T cell tolerance • Deletion • Ignorance Loss of Ts cells Anti-idiotype antibody
Tolerance, T cell tolerance Thymus • Positive selection: cells that are able to recognize and bind to self MHC or to peptide + MHC molecules are selected to grow • Negative selection: cells that recognize and efficiently bind self peptides are auto-reactive cells and undergo apoptotic cell death because they are harmful to the host Cells that pass both positive and negative selection tests “graduate” from thymus ; enter circulation as mature T lymphocytes
Mechanism of tolerance 1- Clonal deletion: Auto-reactive T-cells are eliminated in the thymus following interaction with self-antigen during their differentiation (negative selection). Likewise, differentiating early B cells become tolerant when they encounter cell-associated or soluble self-antigen.
Mechanism of tolerance 2- Clonal anergy: Auto-reactive T cells, when exposed to antigenic peptides lose the second signal, become anergic to the antigen. B cells when exposed to large amounts of soluble antigen down regulate their surface IgM and become anergic.
Ignorance It can be shown that there are T cells and B cells specific for auto-antigens present in circulation. These cells are quite capable of making a response but are unaware of the presence of their auto-antigen. This arises for 2 reasons.
Ignorance The first is that the antigen may simply be present in too low concentration. Since all lymphocytes have a threshold for receptor occupancy which is required to trigger a response then very low concentrations of antigen will not be sensed.
Ignorance The second possibility is a more interesting one. Some antigens are sequestered from the immune system in locations which are not freely exposed to surveillance. These are termed immunologically privileged sites. Examples of such sites are the eye, CNS and testis. Pathologically mediated disruption of these privileged sites may expose the sequestered antigens leading to an autoimmune response.
Mechanism of tolerance 4- Receptor editing: B cells which encounter large amounts of soluble antigen, as they do in the body, and bind to this antigen with very low affinity become activated to re-express their RAG-1 and RAG-2 genes. These genes cause them to undergo DNA recombination and change their antigen specificity.
Mechanism of tolerance 5- Anti-idiotype antibody: produced during the process of tolerization. They prevent the receptor from combining with antigen so inhibit immune response to it. 6- Suppressor cells: Both low and high doses of antigen may induce suppressor T cells, which can specifically suppress immune responses of both B and T cells.
AUTOIMMUNITY- Definition Immune recognition and injury of self tissues (autoimmunity) results from a loss of self tolerance. Autoimmunity is Breakdown of mechanisms responsible for self tolerance Induction of an immune response against components of the self.
Loss of Self Tolerance Most self peptides are presented at levels too low to engage effector T cells those presented at high levels induce clonal deletion or anergy. Autoimmunity arises most frequently to Tissue-specific antigens with only certain MHC molecules present the peptide at an intermediate level recognized by T cells without inducing tolerance.
MHC Association with Autoimmune Disease The level of presented autoantigenic peptide Is determined by residues in MHC molecules These molecules govern the affinity of peptide binding. Autoimmune diseases are associated with particular MHC genotypes.
ClassificationTable 1. Spectrum of autoimmune diseases, target organs and diagnostic tests Disease Organ Antibody to Diagnostic Test Hashimotos thyroiditis Thyroid Thyroglobulin, thyroid RIA, Passive, CF,Organ specific peroxidase hemagglutination Primary Myxedema Thyroid Cytoplasmic TSH receptor Immunofluorescence (IF) Pernicious anemia Red cells Intrinsic factor, Gastric B-12 binding to IF parietal cell immunofluorescence Addisons disease Adrenal Adrenal cells Immunofluorescence Male infertility Sperm Spermatozoa Agglutination, Immunofluorescence Insulin dependent juvenile Pancreas Pancreatic islet beta cells diabetes Insulin resistant diabetic Systemic Insulin receptor Competition for receptor Myasthenia graves Muscle Muscle, acetyl choline Immunofluorescence, receptor competition for receptor Vitiligo Skin Joints Melanocytes ImmunofluorescenceNon-organ Rheumatoid arthritis Skin, kidney, IgG IgG-latex agglutinationspecific joints Systemic lupus Joints, etc. DNA, RNA, nucleoproteins RNA-, DNA-latex agglutination, erythematosus IF
Organ-specific Autoimmune diseases Antigens and autoimmunity restricted to specific organs in the body Hashimoto’ thyroiditis Type I diabetes Multiple sclerosis Grave’s disease Myasthenia gravis
Systemic Autoimmune Disease Antigens and autoimmunity are distributed in many tissues (systemic) Rheumatoid arthritis polymyositis Scleroderma Systemic lupus erythematosus
AUTOIMMUNITY- mechanisms Antibodies Effector T cells
AUTOIMMUNITY- aetiology1. Sequestered antigen Lymphoid cells may not be exposed to some self antigens during their differentiation, They may be late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.). A release of antigens from these organs resulting from accidental traumatic injury or surgery can Result in the stimulation of an immune response and initiation of an autoimmune disease.
AUTOIMMUNITY- aetiology1. Escape of auto-reactive clones The negative selection in the thymus may not be fully functional to eliminate self reactive cells. Not all self antigens may be represented in the thymus Certain antigens may not be properly processed and presented.
AUTOIMMUNITY- aetiology1. Cross reactive antigens Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens. Post streptococcal nephritis and carditis, anticardiolipin antibodies during syphilis Association between Klebsiella and ankylosing spondylitis.
AUTOIMMUNITY- aetiology Infectious triggers: stimulation of co-stimulatory signals, inappropriate MHC II expression, or cytokines Molecular mimicry (cross-reaction) Release of sequestered antigens T cell bypass (pathogen binding to self protein) Superantigen activity/polyclonal activation
AUTOIMMUNITY- aetiology2. loss of suppressor cells.
AUTOIMMUNITY- Diagnosis Diagnosis: Clinical Detection of Ab reactive against soluble antigens by ELISA. Detection of Ab against tissues and cells by IF. In some cases, a biological /biochemical assay may be used (e.g., Graves diseases, pernicious anemia).