Autoimmunity Flashcards
What is Autoimmunity?
Autoimmunity is immune reactions against self antigens owing to the breakdown of immune tolerance.
Do the presence of autoantibodies indicate an autoimmune disease and why?
the mere presence of autoantibodies does not indicate an autoimmune disease exists (autoantibodies in serum of normal individuals or produced after damage to tissues to remove tissue breakdown products).
What is Pathologic autoimmunity?
Pathologic autoimmunity is the presence of an immune reaction specific for some self antigen or self tissue, not secondary to tissue damage but is of primary pathogenic significance, with the absence of another well-defined cause of the disease.
What is the CLASSIFICATION OF AUTOIMMUNITY?
Organ-specific disease: conditions in which the immune responses are directed against a single organ or tissue. Examples are, Type 1 diabetes mellitus and Grave’s disease.
Systemic or generalized disease: conditions in which the autoimmune reactions are against widespread antigens. Examples are, Systemic lupus erythematosus (SLE).
What is Immunologic tolerance?
Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen.
What is Self-tolerance?
Self-tolerance refers to lack of responsiveness to an individual’s own antigens.
How are lymphocytes prevented from recognizing self-antigens?
Because the antigen receptors of lymphocytes are generated by somatic recombination of genes in a random fashion, lymphocytes with receptors capable of recognizing self antigens are generated constantly, and these cells have to be eliminated or inactivated as soon as they recognize self antigens, to prevent them from causing harm.
The mechanisms of self-tolerance can be broadly classified into two groups:
- central tolerance
- peripheral tolerance.
What is Central tolerance?
Central tolerance; In this process, immature self-reactive T and B lymphocyte that recognize self antigens during their maturation in the central (or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless.
Describe Central tolerance in T cells (how does it occur & what protein is involved)
Central tolerance in T cells;
Negative selection or deletion (death by apoptosis), is responsible for eliminating self-reactive lymphocytes from the T-cell pool. A protein called AIRE (autoimmune regulator) is critical for deletion of immature T cells.
In the CD4+ T-cell lineage, some of the cells that see self antigens in the thymus do not die but develop into regulatory T cell
Discuss Central tolerance in B cells
Central tolerance in B cells;
Receptor editing where many of the cells reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens (after recognition of self antigen in the bone marrow).
Self reactive cells undergo apoptosis (if receptor editing does not occur), thus purging potentially dangerous lymphocytes from the mature pool.
What is Peripheral tolerance and the mechanisms involved?
Peripheral tolerance; Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are deleted or muzzled in the peripheral tissues. Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues.
They are;
Anergy
Suppression by regulatory T cells
Deletion by apoptosis
What is Anergy?
Anergy: a phenomenon whereby lymphocytes that recognize self antigens may be rendered functionally unresponsive.
The activation of antigen-specific T cells requires which two signals?
recognition of peptide antigen in association with self MHC molecules on the surface of APCs
a set of costimulatory signals (“second signals”) from APCs.
Discuss the second signal (from the APC) required to activate T cells
These second signals are provided by CD28 (T cell-associated molecule), that bind to their ligands (the costimulators B7-1 and B7-2) on APCs.
If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic.
In normal tissues, costimulatory molecules are not expressed or are weakly expressed on APCs. Thus an encounter between autoreactive T cells and their specific self antigens displayed by these APCs may lead to anergy.
What happens to B-cells in peripheral tissues?
In peripheral tissues, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.
What happens when B lymphocytes express inhibitory receptors?
B lymphocytes also express inhibitory receptors that may play a role in limiting their activation and preventing responses to if B cells encounter self antigen.
Discuss is lymphocyte Suppression by regulatory T cells
Also discuss Mutations in FOXP3
Suppression by regulatory T cells: A population of T cells which functions to prevent immune reactions against self antigens.
The best defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3.
Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells.
Mutations in FOXP3 result in severe autoimmunity in humans; these mutations are the cause of a systemic autoimmune disease called IPEX (an acronym for Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
The inhibitory activity of regulatory T cells may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions.
Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.
Discuss autoreactive lymphocyte Deletion by apoptosis
Deletion by apoptosis: T cells that recognize self antigens may receive signals that promote their death by apoptosis.
It is postulated that if T cells recognize self antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and Bcl-x.
Unopposed Bim triggers apoptosis by the mitochondrial pathway.
What is the Fas-Fas ligand system?
What is the condition called if there is a mutation in the system?
- The death receptor Fas (CD95) is expressed on lymphocytes as well as many other cells, whereas the Fas ligand (FasL) is expressed mainly on activated T lymphocytes.
- The engagement of Fas by FasL induces apoptosis of activated T cells.
- It is postulated that if self antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas mediated apoptosis
- Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells.
- Mutation in the Fas gene in humans is the autoimmune lymphoproliferative syndrome (ALPS).
What is the underlying cause of autoimmune diseases?
How does it arise?
The underlying cause of autoimmune diseases is the failure of tolerance, which allows responses to develop against self antigens.
Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes
susceptibility genes and environmental triggers induce a number of changes that contribute to the development of autoimmunity, which are?
susceptibility genes and environmental triggers induce a number of changes that contribute to the development of autoimmunity:
Defective tolerance or regulation:
There is a failure of the mechanisms that maintain self-tolerance, which is fundamental to the development of autoimmune diseases.
Abnormal display of self antigens:
There is increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens due to enzymatic modifications or from cellular stress or injury ( leading to display of antigenic epitopes that are not normally expressed).
Inflammation or an initial innate immune response:
The innate immune response is a strong stimulus for the subsequent activation of lymphocytes and the generation of adaptive immune responses. Microbes or cell injury may elicit local inflammatory reactions resembling innate immune responses, and these may be critical inducers of the autoimmune disease
What is the role of Susceptibility Genes?
Role of Susceptibility Genes
Most autoimmune diseases are complex multigenic disorders.
The incidence of many autoimmune diseases is greater in twins of affected individuals than in the general population.
And greater in monozygotic than in dizygotic twins, proof that genetics contributes to the development of these disorder
What is the Association of HLA Alleles with Disease?
Among the genes known to be associated with autoimmunity, the greatest contribution is that of HLA genes.
The most striking of these associations is between ankylosing spondylitis and HLA-B27.
Individuals who inherit this class I HLA allele have a 100-200 fold greater chance of developing the disease compared with those who do not carry HLA-B27.
Many autoimmune diseases are associated with different class II HLA alleles.
It is also important to understand that different HLA alleles may contribute to a disease but their presence is not, by itself, the cause of any disease. Thus, vast majority of individuals who inherit HLA-B27 allele never develop ankylosing spondylitis.
