Immune tolerance & Autoimmunity Dr Ghada Barakat lecturer, Med Microbiology & Immunology
Immune tolerance & AutoimmunityDr Ghada Barakat
lecturer, Med Microbiology & Immunology
Contents
Introduction1
2
3 Autoimmunity
Tolerance
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
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 responseTolerancePhysical form of AgLarge,aggregated, complexSoluble, smaller, less complex
Route of AgSC or IMOral or IV
Dose of AgOptimal doseVery large (sometimes very small)
Age of responding animal
Older and immunologically mature
Newborn, immunologicall immature
Differentiation state of cells
Fully differentiated; memory T and B
Relatively undifferen: B, T cells
Tolerance, mechanism
B cell tolerance • Deletion• Anergy• receptor editing
T cell tolerance• Deletion• Ignorance
Loss of Ts cells Anti-idiotype antibody
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
Tolerance, T cell tolerance
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.
Mechanism of tolerance
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
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 withAutoimmune 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.
Classification
Table 1. Spectrum of autoimmune diseases, target organs and diagnostic tests
Organ specific
Non-organ specific
DiseaseOrganAntibody toDiagnostic Test
Hashimoto's thyroiditisThyroidThyroglobulin, thyroid peroxidase
RIA, Passive, CF, hemagglutination
Primary MyxedemaThyroidCytoplasmic TSH receptorImmunofluorescence (IF)
Pernicious anemiaRed cellsIntrinsic factor, Gastric parietal cell
B-12 binding to IF immunofluorescence
Addison's diseaseAdrenalAdrenal cellsImmunofluorescence
Male infertilitySpermSpermatozoaAgglutination, Immunofluorescence
Insulin dependent juvenile diabetes
PancreasPancreatic islet beta cells
Insulin resistant diabetic SystemicInsulin receptorCompetition for receptor
Myasthenia gravesMuscleMuscle, acetyl choline receptor
Immunofluorescence, competition for receptor
VitiligoSkin JointsMelanocytesImmunofluorescence
Rheumatoid arthritisSkin, kidney, joints
IgGIgG-latex agglutination
Systemic lupus erythematosus
Joints, etc.
DNA, RNA, nucleoproteins RNA-, DNA-latex agglutination, IF
Organ-specific Autoimmunediseases
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- aetiology
1. 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.
2. 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- aetiology
3. 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- aetiology
4. loss of suppressor cells.
AUTOIMMUNITY- aetiology
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).
AUTOIMMUNITY- Treatment
Treatment: Anti-inflammatory e.g.corticosteroid Immunosuppressive (cyclosporin) Anti-idiotype antibodies, antigen peptides,
anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc.