Tolerance & autoimmunity 1
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Transcript of Tolerance & autoimmunity 1
TOLERANCE & AUTOIMMUNITY 1
Aims of sessions
Promote awareness of: Developmental aspects of
autoimmunity Induction and loss of central tolerance Thymic selection Peripheral tolerance mechanisms Overview of autoimmune disease
Introduction
Concept of Autoimmunity was first predicted by Paul Ehrlich (‘horror autotoxicus’)
Gene rearrangements that occur during lymphocyte development are random
Self reactive lymphocytes are normally removed or held in check by a number of mechanisms (Self-tolerance)
Autoimmunity is a failure or breakdown of the mechanisms of self tolerance
Autoimmunity and tolerance
Tolerance is a state of immune non-responsiveness to self
Tolerance is generated by two main mechanisms:
1. Central tolerance2. Peripheral tolerance Autoimmunity reflects a loss of (self!)
tolerance Involves autoreactive B and T cells
Cross section of the thymus
Pro T cell route
Stages in T cell development
Stem cell
Pro-T cell
DN1
DN2
DN3
DN4
DP
SP
Pre-T cell
Selected Surface markers
c-kit CD44 CD25
+ + -
+ + -
+ + -
+ + -
+ + +
- - +
- - -
CD4+ & CD8
CD4 or CD8 immature
SP mature naïve T cell
CD3
TCR events
Germ-line configuration - unrecombined
b genes recombined. TCR β chain expressed (Dβ to Jβ rearrangements) to Vβ to DJβ rearrangements
a genes recombined. TCR a chain expressed
Migratory route of the developing T cell through the Thymus
+ve & -ve selection in a nutshell
Autoimmune Regulator (AIRE) Gene
AIRE modulates transcription of peripheral self-antigens in the thymus presented by MHC molecules to maturing T cells
Immature thymocytes with high affinity receptors for self antigens in the thymus die by apoptosis
Negative selection in double positive T cells occurs in the thymic cortex or newly generated single positive cells in the medulla
Case study: APS1 aka APECED
Mutations in the AIRE genes associated with autoimmune polyendocrine syndrome type1 (APS 1)
APS 1 is extremely rare-only about 500 cases worldwide
Clinical diagnosis depends on 2 out of 3 of the following symptoms
1. Chronic mucotaneous candidasis2. Primary adrenocortical failure3. Hypoparathyroidism
Central tolerance in T cells
Central tolerance does not delete T cells autoreactive to organ-sequestered antigens and cryptic epitopes
Subset of these T cells are potentially pathogenic
These T cells must be kept tolerant by: Deletion maintenance of immunologic ignorance functional inactivation (anergy) suppression
A Quick Reminder
Peripheral T Cell Tolerance Overview
Mature T cells which recognise self antigen in peripheral tissues are rendered incapable of responding to these antigens
3 Mechanisms of action Anergy (1st signal through TCR with no 2nd or weak
co-stimulatory or innate immune signal) leads to functional unresponsiveness
Engagement of inhibitory receptors e.g. CTLA-4 (Inhibition)
Peripheral T Cell Tolerance Overview
Suppression via regulatory T cells
Deletion no co-stimulation results in (Apoptosis-activation induced cell death)
Inhibitory receptors (Cytotoxic T Lymphocyte Antigen-4)
CTLA-4 inducible in CD4+T cells-binds to B7 on APCs
Serves as a negative regulator of T-cell activation and proliferation
Prevents co-stimulation of CD28 Has a higher affinity than CD28 for B7 (CD80
& CD86) CTLA-4 may also remove B7 from APC
surfaces Unknown whether it induces ‘anergy’ in
CD8+T cells
Programmed Death-1
PD-1 has 2 ligands PD-L1 and PD-L2 Influences both central and peripheral
tolerance mechanisms Thought to work synergistically with CTLA-
4 Regulates the threshold for T cell
activation and quantities of cytokines produced
Maybe a way that tumours evade immune attack (by expressing PD-L1/2)
Important points to note
Certain features of protein antigens can favour tolerance over an immune response
1. Persistence 2. Location3. Presence of adjuvant4. Characteristics of APCs
Regulatory T cells
Subset of CD4+ T cells Express IL-2 receptor α chain (CD25) and Foxp3 a member of the forkhead family of transcription factors
Also express high levels of CTLA-4 2 types of T regs have been identified
Natural-thymus and adaptive-induced in the periphery
Function to supress immune responses and maintain self-tolerance
In mouse models, T regs can be used to inhibit immune responses in autoimmunity, GVHD and allergic diseases
Maintenance & Mechanisms of action of T regs
Dependent on TGF-β and IL-2 TGF-β stimulates expression of Foxp3 IL-2 promotes differentiation of T cells
into regulatory cells IL-2 also activates STAT5 T cell activation can be suppressed in
the lymphoid organs as well as in the tissues during the effector phase via a number of mechanisms
How are regulatory T cells generated?
Case study: IPEX syndrome
Male baby developed atopic dermatitis shortly after birth. Later, he developed diarrhoea and failure to thrive
Duodenal biopsy revealed almost total villous atrophy with a dense infiltrate of plasma cells and T cells
At 6 months diagnosed with Type 1 Diabetes FACS analysis of PBMCs revealed a lack of CD4
CD25 T cells and CD4 Foxp3+ cells Sequencing of FOXP3 gene revealed a missense
mutation, confirming diagnosis of IPEX
IPEX treatments
Total parenteral nutrition If necessary RBC and platelet transfusions Insulin injections Immunosuppressive drugs have proven
effective in some patients-usually only partially and for a limited time
Bone marrow transplantation advisable Only known effective cure-HLA matching
required
Inhibitory Cytokine Release
Interleukin-10 inhibits the production of IL-12 by activated macrophages and DC’s
IL-10 inhibits expression of co-stimulators & MHC Class II
IL-10 is thought to play a key role in immune control within mucosal tissues and in particular the GI tract
Tumour Growth Factor-β inhibits T cell proliferation and effector functions and macrophage activation
T regs switch to Th17 subset regulated by action of TGF-β and pro-inflammatory cytokines
Activation Induced Cell Death
Key mechanism underlying AICD is the ligation of Fas (CD95-aka TNFRSF6) by its ligand (FasL)
Cell death that occurs as a due exposure of mature T cells to antigen
Bim maybe triggered by T cells that recognise self antigen in the absence of co-stimulation
Defects in the Fas pathway in humans are associated with Autoimmune Lymphoproliferative Syndrome
Case study: ALPS
18 month old girl with splenomegaly and lymphadenopathy
Elevated lymph count and serum IgG, IgM and IgA
FACS analysis revealed raised B cell count 29% (normal range 5-15%)
65% CD3 positive T cells (normal range 61-84%)
Of these 14% were CD4 and 18% were CD8
Vast majority of the remainder where _____ T cells
ALPS continued
Most of the cells expressed the TCRαβ T cell receptor
Normally these are absent or constituent <2% of circulating T cells
Lymph node biopsy from neck revealed enlargement of follicles (hyperplasia)
No infectious agents cultured from the LN
No oligoclonality of the TCR ruled out malignancy
At 18 yrs she developed idiopathic thrombocytopenic purpura
ALPS Treatment
Anti-inflammatory steroids (prednisone) and the immunosuppressant (cyclosporin A) were prescribed
LNs reduced in size rapidly after therapy but increased again when therapy was discontinued
In some cases splenectomy can be effective in controlling thrombocytopenia and anaemia
So far bone marrow transplant has been used successfully in two cases (one of which was homozygous) with a severe, worsening clinical phenotype
B Cell Central Tolerance
Central B cell tolerance takes place in the bone marrow
Important for maintaining unresponsiveness to thymus-independent self antigens
Immature B lymphocytes that recognise self antigen with high affinity change their specificity (receptor editing) or are deleted
B cells that weakly bind self antigen become anergic and exit the bone marrow
B Cell Receptor editing (mediates negative selection in the bone marrow)
Immature B cells recognize self antigens present in high concentrations
Especially if self antigens are displayed in multivalent form
Cross linking leads to reactivation of RAG1 and RAG2
VJ recombination in the Ig Kappa light chain gene locus
A new Ig light chain is expressed-creating a new BCR with new specificity
Peripheral B Cell Tolerance
Mature B Cells in the periphery become anergic or die by apoptosis in the absence of specific T helper cells
In the absence of infection, if newly mature B cells encounter strongly cross-linking antigen they will undergo clonal deletion
Mature B cells that encounter and bind abundant soluble antigen become anergized (chronic exposure to soluble antigen)
PTPN22 risk allele
One of the strongest risk factors for AD outside of the MHC
PTPN22 encodes lymphoid protein tyrosine phosphatase (Lyp) expressed exclusively in immune cells
Locus is located on chromosome 1p13.3-13.1 Decreased B cell signalling leads to defective
central B cell tolerance, allowing accumulation of mature naive autoreactive B cells
Also thought to play a role in T cell selection
Immune privilege
Sequestered Antigens
Molecular mimicry
Overview of autoimmune disease
Between 5-7% of the population in the developed world has an autoimmune disease
Autoimmune diseases are more prevalent in woman than men
Familial clustering Incidence of disease is on the increase Clinicians tend to categorise disease as
either systemic (e.g. SLE) or organ-specific (type 1 diabetes mellitus)
Autoimmune disease is multifactorial
Criteria for definition of an Autoimmune disease
1. Serum autoantibodies and/or cell mediated events are found in the disease
2. Autoantibodies and/or T cells are found at the site of tissue damage
3. Levels of autoantibody or T cell response reflect disease activity
4. Reduction of Autoimmune response leads to improvement
AI criteria cont.…..
4. Transfer of antibody or T cells to a second host leads to development of Autoimmune disease in the recipient
5. Immunization with autoantigen & consequent induction of Autoimmune response causes disease