Exam 2: Autoimmunity Flashcards
1
Q
Autoreactive Lymphocytes
A
- Low levels of autoreactive T and B cells common
- Usually harmless due to regulatory mechanisms
- In 2-5% of population ⇒ anti-self-response robust enough to cause clinically significant damage ⇒ autoimmune disease
2
Q
Autoimmune Diseases
Characteristics
A
Adaptive immunity inappropriately targets self-antigens due to loss of self-tolerance.
Chronic, progressive, and self-perpetuating
- Persist because auto-Ag cannot be removed
- If autoreactive reaction crosses threshold, resulting tissue damage can further up-regulate immune response
3
Q
Autoimmune Diseases
Susceptibility
A
-
Generally multifactorial
- Genetics
- Environmental factors
- Stochastic events
- Few are due to single gene disorders
4
Q
Factors Leading To
Autoimmunity
A
- Breakdown or failure of tolerance mechanisms
- Genetic susceptibility
- Uncontrolled or misdirected response to foreign antigen
- Injury
- Hormonal influences
5
Q
Genetic Susceptibility
A
-
MHC Alleles
- Most associated with MHC class II
- Alkylosing spondylitis shows strongest correlation (HLA-B27)
-
Most encode residues in the peptide binding groove or regions near the groove
- Determines peptide binding, T cell recognition, and selection during thymic maturation
-
Non-MHC Alleles
- Role in development and regulation of immune responses
- Many in non-coding regions
-
Few single-gene abnormalities identified that cause autoimmunity
- High penetrance
6
Q
Infection
&
Autoimmunity
A
-
Release of sequestered self-Ag
- Break cell/tissue barriers
- ↑ concentration of specific self-Ag
- Triggers activation of un-tolerized (ignorant) lymphocytes
-
Triggering a bystander effect
- Infection upregulates costimulators on APCs
- Naive non-tolerant T-cells accidently provided both signals by APC presenting self-Ag
-
Altering self-proteins
- Infectious agents bind to self-Ag making them appear foreign
- As immune response develops, epitope spreading could lead to autoimmunity
-
Triggering a cross-reactive response due to molecular mimicry
- Foreign-Ag induces T/B cells with cross-reactivity to self-Ag
- Causes naive cells to expand to autoreactive effector cells
-
Overcoming anergy by the polyclonal activation of lymphocytes
- T-cell activation by superantigen
- B-cell activation by LPS or Epstein-Barr virus
- Can activate previously tolerized or anergized autoreactive cells
7
Q
Changes in Anatomical Structures
&
Autoimmunity
A
Inflammation, ischemia, or trauma can result in the release of self-Ag.
-
Post-traumatic uveitis and orchitis
- Follows damage to an immunoprivileged site of the eye
-
Sympathetic ophthalmia
- Rare bilateral granulomatous uveitis
- Follows ocular trauma or surgery to one eye
- Both eyes affected once tolerance or clonal ignorance lost
8
Q
Gender Differences
A
Most autoimmune diseases have high incidence in women.
Thought to be secondary to hormonal changes.
Theories include:
- ♀ have more vigorous immune responses overall
- ♀ with more TH1 like responses
- Immunostimulatory role of estrogen and prolactin
- Fetal cells in maternal circulation
- Maternal cells in male circulation
9
Q
Self-Tolerance Failure
A
-
Defects in deletion
- ∆ central tolerance
-
Defects in apoptosis
- ∆ central tolerance and AICD
-
Defects in anergy
- Breakdown of T-cell anergy
-
Inadequate Treg cell generation
- Ex. IPEX
10
Q
Autoimmune Disease
Progression
A
- Predisposition of an individual to autoimmunity
-
Autoimmune event initiated by an environmental trigger or stochastic event
- Loss of self tolerance
- Stimulation of autoreactive lymphocytes
-
Autoimmune attack releases additional self-Ag which are not eliminated in an efficient manner
- Propagation of autoimmune response
- Response against ↑ # of self-Ag
- Epitope spread ⇒ recognition of additional epitopes within the recognized self-Ag
- Development of clinical features
11
Q
Organ-specific
vs
Systemic Disease
A
Determined in part by distribution of auto-antigen.
-
Organ specific autoimmune diseases
- Often involve autoreactivity against a single antigen or target cell
- Can result in systemic symptoms
-
Systemic Disease
- Tends to be immune complex mediated
- Involves autoreactivity against multiple self-antigens
12
Q
T vs B
Mediated Damage
A
Various effector mechanisms responsible for tissue injury.
Most autoimmune diseases have varying roles for T-cells and B-cells in pathogenesis.
Diseases classified as B cell or T cell mediated but…
Most B-cell responses are T-cell dependent.
B-cells can act as important APC for T-cell activation.
13
Q
Multiple Sclerosis
Pathophysiology
A
Prominent T-cell activity.
Considered a type IV hypersensitivity.
- Mediated by autoreactive CD4+ T-cells
- Inflammatory process upregulates Fas on oligodendrocytes making them targets for FasL expressing T-cells
- Auto-Ag includes PLP, MBP, and others
- IL-17 involved suggesting TH17 cell involved
- Results in demyelination or destruction of myelin sheaths in CNS
- Relapsing-remitting course or chronic progressive form
- Hypothetical triggers:
- Release of sequestered myelin Ag s/p infection or trauma
- Molecular mimicry d/t immune response to virus with “neuro-epitope”
14
Q
Daclizumab (Zenapax)
(MS)
A
- Humanized mAb for IL-2R α-subunit
- Shown to ↓ lesions
- ? impact on T cell ± NK cell
15
Q
Natalizumab (Tysabri)
(MS)
A
- Humanized mAb for VLA-4 on activated T cells
- VLA-4 : VCAM on BBB for firm adhesion
- Reduces progression of MS
- But ↓ CNS T cell immunity ⇒ reactivation of latent viruses
- Can lead to development of progressive multifocal leukoencephalopathy (PML)
19
Q
Graves’ Disease
A
Prominent B-cell activity.
Considered a non-cytotoxic type II hypersensitivity.
- Auto-Ab causes constitutive activation of TSH receptor
- Can be transmitted from mother to infant via placental IgG
- High T3 and T4 but low TSH
- ↑ in general metabolic activity, sweating, hot flashes, nervousness, weight loss, goiter, exophthalmos
- Serum contains autoAb to thyroid components
- Thyroglobulin, cell surface Ag, microsomes, TSH receptor
- Possible triggers:
- Aberrant expression of MHC class II d/t viral infection
- Ag cross-reactivity between TSH receptor & Yersinia enterolytica
- Treatment includes:
- Anti-thyroid drugs ⇒ reduce production of thyroid hormones
- Thyroidectomy
- Radioiodine ablation
20
Q
Pernicious Anemia
A
Prominant B-cell activity.
Considered a type II hypersensitivity.
- Auto-ab against intrinsic factor
- IF needed for absorption of Vit B12
- Erythropoiesis deficient leading to macrocytic anemia
- Treatment with Vit B12 supplementation
21
Q
Goodpasture Syndrome
A
Prominent B-cell activity.
Classic type II hypersensitivity.
- Auto-Ab bind Ag epitope in basement membranes
- Results in:
-
Recurrent alveolar hemorrhage
- For Ab deposition, additional lung injury must occur which increases alveolar-capillary permeability
- Events that induce lung inflammation ↑ risk
- Rapidly progressive severe glomerulonephritis
-
Recurrent alveolar hemorrhage
-
Treatment includes:
- Plasmapheresis
- Prednisone
- ACE inhibitors
22
Q
Systemic Lupus Erythematous
(SLE)
A
Combined T and B cell activity.
Considered a type III hypersensitivity.
- High titers of antinuclear auto-Ab and nuclear debris form immune complexes
- Often also auto-Ab against platelets, WBCs, RBCs
-
Complexes deposit & activate complement components
-
Kidney
- Directs accumulation of granulocytes within glomeruli
- Destruction of blood vessel wall and nephron
- “Lumpy bumpy” morphology with immunofluorescence
- Glomerulonephritis most damaging
-
Skin
- Butterfly rash on face
-
Kidney
-
Auto-reactive T-cells play a critical role
- Can activate auto B cells with more wide range of reactivities
-
Abnormalities in macrophage scavenger function ↑ likelihood of SLE
- Poor clearance of apoptotic cells
- Normally hidden Ag in blebs released
- Stimulates autoreactive cells
- Treatment with immunosuppresive drugs
23
Q
Rheumatoid Arthritis
(RA)
A
Combined T and B cell activity.
- Inflammatory process in joints results in dysfunction and deformity
- Th1 cells and macrophages play dominant role in RA development
- AutoAb Rheumatoid factor (RF) with role in inflammation and neutrophil recruitment but likely not causative
- Binds IgG allowing ↑ complement activation
-
Early stage:
- Synovial membrane and cavity contains infiltrating neutrophils, lymphocytes, and plasma cells
-
Advanced stage:
- Highly vascular inflammatory tissue ⇒ pannus
- Mostly lymphocytes, plasma cells, macrophages, and fibroblasts
- Eventually undergoes calcification
24
Q
Tofacitinib
(Xeljanz)
A
25
Q
Myastenia Gravis
A
Combined T and B cell activity.
Type II Hypersensitivity
-
Auto-Ab bind Ach receptor at NMJ
- Block interaction of ACh with receptor
- Interacts with regions near the receptor and physically hinder ACh access
-
Bound Ab fix complement
- Induces destruction of the folding membrane
-
IgG can cross placenta
- Cause transient disease in newborn
- T-cells can transfer disease in animal models
-
Treatment includes:
- Plasmapheresis
- Exchanges with normal plasma
- Thymectomy
- Acetylcholinesterase inhibitors
