Tolerance & autoimmunity

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.


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.


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.


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.


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.


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


4. 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).

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.

Education

Tolerance & autoimmunity