Autoimmunity Flashcards
Avoids excessive lymphocyte activation and tissue damage during normal immune responses to pathogens and infections
Immune Regulation
Immune regulation prevents inappropriate immune responses and reactions specific for
Self antigens
Failure of tolerance to control immune mechanisms leads to
Autoimmunity
A specific unresponsiveness to a self antigen
Immunological self-tolerance
A breakdown or failure in the mechanisms that mediate self-tolerance leads to
Autoimmunity
What are the two types of tolerance?
Central tolerance and peripheral tolerance
The selection of B cells (bone marrow) and T cells (thymus)
Central tolerance
Central tolerance is not perfect. Some self-reactive T cells escape thymic
Negative selection
These T cells that escape are controlled by
Peripheral tolerance
The principal fate of lymphocytes that recognize self is
Death
Some T cells in the thymus and periphery differentiate into
Regulatory T lymphocytes
What is the phenotype of regulatory T cells?
CD4+
- high IL-2R
- Low IL-7R
- Foxp3+
A human autoimmune disease called Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by
Foxp3 mutations
Most commonly manifests with early onset, insulin-dependent diabetes mellitus (T1 diabetes)
IPEX
Most children affected with IPEX die within the
First 2 years of life
One major cell group with promising therapeutic regulation is
Tregs (T-regulatory cells)
In the thymus, T cell selection occurs on
MHC-peptide
But not all self proteins are expressed in the thymus. So how do proteins from tissue-specific genes get expressed in the Thymus?
AIREs
Rare autosomal recessive disorder with the hallmarks of Chronic mucocutaneous candidiasis (yeast infections), Chronic hypoparathyroidism, and Addison’s disease
Autoimmune Polyglandular Syndrome (APS) or APECED
APs and APECED will eventually result in other autoimmune diseases such as
Type 1 diabetes
Patients with APS and APECED have a mutation in the transcription factor
AIRE
Regulates autoimmunity by promoting the ectopic expression of peripheral tissue restricted antigens in the thymus
AIRE
Central tolerance is not perfect. Some self-reactive B cells escape negative selection in the
Bone Marrow
These B cells are controlled by
Bone Marrow
Relating to, or caused by autoantibodies or T cells that attack molecules, cells, or tissues of the organism producing them
Autoimmunity
We are supposed to be tolerant to self-antigens so how is autoimmunity initiated?
Reduction/loss in Treg activity
Autoimmune diseases usually arise
Spontaneously
The disease is restricted to specific organs of the body. Autoantigens from one or a few a organs are recognized and thus, the disease is limited to these organs
Organ-specific autoimmunity
Autoimmune disease that effects the whole body
Systemic autoimmune diseases
RA, SLE and scleroderma are examples of
Systemic autoimmune diseases
The genetic basis of autoimmunity is that it tends to run in
Families
Are mostly multigenic
Human AI diseases
Have a major genetic association with autoimmune diseases
MHC genes
In many cases MHC link has been tracked back to peptide presentation (and subsequent activation of
CD4 or CD8 T cells
What is the HLA association of RA?
DR4 + DR1
What is the HLA association of Type 1 DM?
DR3 + DR4
Some variants predispose to multiple autoimmune diseases providing confirmation that many diseases share
Common pathways
Multiple genes are involved in predisposition to each
AI disease
Autoimmunity development is also influenced by
Environmental Factors
Inbred mice that are genetically identical and are destined to get diabetes
NOD mice
Can lead to autoimmunity by causing T cells and antibodies to become activated, which results in the potential for them to cross-react with self antigens
Infection
A non-self protein that looks like self (mimicry) when delivered via a pathogen provides all the signals necessary to activate the immune system and cause
Autoimmunity
Infection provides an environment that promotes
Lymphocyte activation
To serve as an example of this, NOD mice have an increase in the severity of diabetes when infected with
Coxsackie virus
Viral infection leads to inflammation, tissue damage and release of sequestered islet antigens and subsequent generation of
Self-reactive T cells
Coxsackie B4 nuclear protein is a mimic of human
GAD
Excessive prevention of early childhood exposure to dirt and pathogens can stunt the development of the immune system. This is called the
Hygiene hypothesis
Autoimmune disease can be triggered by
Drugs
What are the two types of autoimmunity that can be caused by drugs?
- ) Immunological response (reversible)
2. ) True drug autoimmunity
The immunological response is also called
Drug hypersensitivity
An example of drug hypersensitivity is
Acacavir Hypersensitivity Syndrome (AHS)
An anti-retroviral (reverse transcriptase inhibitor) used to treat HIV
Acacavir
Progresses initially independently of drug withdrawal requires some form of immunosuppressive treatment
A true autoimmune process induced by a drug
Autoimmune diseases tend to be chronic because the initiating trigger often cannot be
Eliminated
An immune response starts with one antigen but quickly spreads to many other antigens. This is called
Epitope Spreading
In an organ-specific T cell-mediated autoimmune disease, various genetic loci may confer susceptibility to autoimmunity, in part by influencing the maintenance of
Self-tolerance
Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of
Self-reactive T cells
What is the prototypic immune complex mediated disease?
Systemic Lupus Erythemtosus (SLE)
An anti-IFN-a antibody (type I interferon) used to treat SLE
Sifalimumab
What are three other new strategies for treating SLE?
TLR inhibition, B cell depletion, and Anti-BAFF antibodies
An IL-1 antagonist used to treat RA
Anakinra
Tocilizumab is used to treat RA. It functions as an
Anti-IL-6 receptor antibody
