02: Mechanisms of Autoimmunity Flashcards
What is the lifetime risk of developing a systemic autoimmune disease?
- 8.4% of women (1 in 12)
- 5.1% of men (1 in 20)
- Most common being RA
What is the natural history of a rheumatic disease?
- Genetic predispostion
- How and which peptides are presented
- Self T cell repertoire selection (basis of adaptive immunity)
- Autoimmunity
- Loss of tolerance of one or a few T cell clones
- Progressive T cell clonal expansion and activation
- AAb production starts, reflecting inappropriate self-recognition
- Autoimmune disease
- Inflammation and target organ damage
- Autoimmune response progressively intensifies and spreads, passing threshold when it acquires ability to damage tissue
What is the most important genetic determinant of susceptibility to autoimmune disease?
Particular MHC alleles (located on chromosome 6)
What are the MHC I associated diseases?
- Ankylosing spondylitis
- Psoriatic arthritis
- Psoriasis
NB1: CD8 T cells
NB2: no AAbs
What are the MHC II associated diseases?
- SLE
- Sjogren’s syndrome
- RA
NB1: CD4 T cells
NB2: AAbs
How does abberent binding of certain MHC alleles result in autoimmunity?
- MHC molecules associated with susceptibility anomolously bind certain self-peptides (e.g., in T1DM, diabetogenic peptide binds MHC II in modified manner which triggers T cell response)
- MHC molecule drives autoimmune dz by allowing topologically altered binding of target peptides –> pathogenic T cell clones
How does Treg production failure result in autoimmunity?
- MHC molecules are expressed on dendritic cells in the thymus
- MHC molecules fail to generate functional Tregs during negative selection phase of TCR repertoire formation
- Tregs normally modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease
What is the “central abnormality” of autoimmunity?
- T cell clone specifically recognizes and persistently responds to self-peptide anomalously presented by a particular allomorphic MHC molecule.
- T cell is not “tolerant” of self p-MHC
- T cell transitions from quiescent to strongly responding
What is the key point with regards to susceptibility genes and autoimmune disease?
Each of these geens by itself confers a beneficial subphenotype (e.g., cancer destruction, waste removal); it is the combination of these subphenotypes that confers the risk for shifting beneficial self-recognition to autoimmunity
What patients will have AAbs that react with nuclear antigens at 1:160?
- SLE patients
- Patients with other autoimmune diseases
- Less than 1% of healthy/normal patients
Describe the role of cognate B cells in autoimmunity
- Recruited by CD4 T cells
- B cells produce ↑AAbs (↑titers)
- Isotype switches from surface IgM to secreted IgG
- Maturation to higher-affinity AAbs through somatic mutation
- Spreading of immune response to additional epitopes on initial autoantigen and additional molecules
True or false: Natural ANAs are often seen transiently with B cell stimulation.
True; this may occur with infection of B cells by EBV during infectious mononucleosis; these AAbs are not antigen driven, lack T cell help and are not part of an immune response.
Most AAbs in SLE are directed against what proteins?
- DNA/protein complexes
- RNA/protein complexes
- Cell membrane structures
- IC molecules expressed on cell surface during activation or apoptosis
- Components of serum or connective tissue (e.g., C1q, type IV collagen)
What are the common AAbs against DNA/protein complexes?
-
Anti-ds DNA
- Specific for SLE (>50-75% of pts)
- **Anti-ss DNA **very non-specific
-
Anti-histone
- Non-specific for SLE (30-40%)
- **Drug (hydralazine) lupus **(>90%)
What are the common AAbs against RNA/protein complexes?
- Anti-Sm: Specific for SLE (30%)
-
Anti-U1 RNP: Non-specific for SLE (30%)
- U1-RNP is a component of the spliceosome
- AAbs give speckled ANA pattern
- Anti-Ro (anti-SS-SA) & anti-La (anti-SS-B): present in Sjogren’s syndrome (>95%), subacute cutaneous lupus erythematous (~100%), SLE (10-60%), neonatal lupus (100%)
