Autoimmunity

Autoimmunity
o At least 3 requirements should be met before a disorder is categorized as truly due to
autoimmunity
Presence of an immune reaction specific for some SELF-Ag or self tissue
Evidence that such a reaction is not secondary to tissue damage but is of primary
pathogenic significance
Absence of another well defined cause of the disease
Spectrum
o Organ-specific
Type I diabetes mellitusbeta- Islet of Langerhans in pancreas
o Systemic Autoimmune diseases generalized, antibodies to DNA or histones, etc
SLE
o Good pasture Syndrome
In between: renal and pulmonary systems glomerular and alveolar basement membrane
OrganS specific
Tolerance
o Immunological tolerance is the phenomenon of unresponsiveness to an Ag as a result of exposure
to lymphocytes to that Ag
o Self tolerance refers to lack of responsiveness to an individuals OWN Ag and it underlies our ability
to live in harmony with our cells and tissues
o Mechanisms of Tolerance: 2 groups
Central and Peripheral Tolerance
o Immature self reactive T and B lymphocyte clones that recognize self Ag during their maturation in
the central [or generative] lymphoid organs [THYMUS: for T cells and BONE MARROW: for B cells]
are KILLEd or rendered harmless in the THYMUS: negative selection or DELETION by Apoptosis
Only those T cells that are ABLE to recognize adequately with MHC molecules are ALLOWED
to proceed: positive selection
o AIRE [autoimmune regulator] stimulates expression of some peripheral tissue restricted self Ags
in the thymus
o In CD4+ T cells lineage, some of the cells that are self Ag in the thymus dont die but develop into
the regulatory T cell
o Developing B cell
Receptor editing
If Receptor editing does not occur, the self reactive cell undergo APOPTOSIS
ANERGY: sustained state of unresponsiveness
o 2 mechanisms of T cell ANERGY
The cell lose their ability to trigger biochemical signals from the TCR complex, in part
because of activation of ubiquitin ligases and proteolytic degradation of receptor associated
signaling proteins
T cells that recognize self Ag receive an inhibitory signal from receptors that are
structurally homologues to CD28 but serve the opposite functions
B cells encounter self Ag in peripheral tissues, especially in the absence of specific
helper T cell, the B cell become UNABLE to responds to subsequent Antigenic
stimulation and may be excluded from lymphoid follicles death
Suppression by regulatory T cells
Regulatory T cells develop mainly in the thymus as a result of recognition of self Ag,
but they may also be induced in peripheral lymphoid tissues
Autoimmunity
CD4+ that constitutively express CD25, the alpha chain on the IL-Receptor, a
transcription factor of the forkhead family: FOXp3
Deletion by activation-induced cell death
CD4+ T cell that recognize self Ag may receive signals that promote their death
apoptosis
2 mechanisms
o It is postulated that if T cell recognize self Ag, they may express a pro-apoptotic member of the Bcl
family: Bim WITHOUT antiapoptotic members of the family Bcl-2 and Bcl-x
o 2
nd
mechanism of activation induced death of CD4+ T cell and B cell involved the Fas-Fas ligand
system
o self reactive B cell may also be delted by FasL on T cell engaging Fas on the B cell
Role of Genes
o Incidence greater in monozygotic than dizygotic twins
o Greated contribution is that of HLA genes
o Multiple NON MHC genes are associated with various diseases
o Some of the genes are disease specific but many of the associations are seen in multiple disorders
o Polymorphisms in a gene called: PTPN-22 which encodes a protein tyrosine phosphatase
Rheumatoid arthritis, type I diabetes, several other autoimmune diseases
o Polymorphisms in gene for NOD-2
Chrons Disease: form of inflammatory bowel disease, especially in certain ethnic
populations
o Genes encoding the IL2 receptor [CD25] and IL7 receptor ALPHA chains are associated with
Multiple Sclerosis and others
o