Flashcards in Exam #3: Immuopathology II Deck (54):
What is conditioning regime?
Irradiation therapy to destroy the immune system and create a graft bed
What is timeline for acute GVHD?
Days to weeks post engraftment
What is the mechanism of acute GVHD?
Immunocomptent T-cells in the donor bone marrow recognize recipient HLA antigens as foreign & react to them
- CTL response= direct destruction
- CD4+= cytokines production and inflammation
What are the manifestations of acute GVHD? Why?
Mainly the immune system and the epithelial of the skin, liver, and intestines are effected
- Skin= dequamating rash
- Liver= small bile duct destruction leading to jaundice
- Intestines= mucosal destruction leading to bloody diarrhea
What is chronic GVHD?
Follows resolution of acute CVHD or may evolve insidiously
What is the mechanism of chronic GVHD?
Autoreactive T-cells deried from donor stem cells that cannot be clonally deleted due to immune compromise of recipient
What are the manifestations of chronic GVHD?
Generally, this is a worsening of acute GVHD that mimics systemic sclerosis
- Destruction of skin appendages and fibrosis of the dermis
- Chronic liver damage leading to jaundice
- GI damage leading to esophageal stricture
****Patients also experience recurrent life-threatening infections
What is bronchiolitis oboliteratans?
Obstructive lung disease that results from chronic GVHD
Generally, what are autoimmune diseases?
Immune reactions against self-antigens
What are systemic autoimmune diseases?
Connective tissue or collagen-vascular diseases that target widely distributed intracellular molecules
Generally, what are the criteria for the diagnosis of an autoimmune disease?
1) Immune reaction for a self-antigen or self-tissue
2) Reaction is NOT secondary to tissue breakdown but is PRIMARY
3) Absence of other well-defined cause of disease
What are the two general mechanisms of self-tolerance?
1) Central tolerance
2) Peripheral tolerance
What is central tolerance?
Process by which self-reactive B & T-cells are killed during their maturation process in the central lymphoid organs i.e. bone marrow & thymus
- Negative selection= T-cells, random rearrangement of somatic genes generates indiscriminate lymphocytes; these cells are presented with self antigens & those that react, die by apoptosis
- Receptor editing= auto-reactive B-cells in the bone marrow get another shot at gene rearrangement to be non-self reactive
What is peripheral tolerance?
Process by which auto-reactive B & T-cells are silenced in peripheral lymphoid organs i.e. lymph nodes
What are the mechanisms of peripheral tolerance?
- T-cells--normal tissues do NOT express the costimulatory molecules needed for activation--T-cells that react to self-antigen undergo a silencing reaction
- B-cells--need helpter T-cells for activation, without, also undergo silencing reaction
Suppression by regulatory T-cells
Deletion by activation induced cell death= CD4+ T-cells that recognize self-antigens recieve signals that promote their apoptosis
What locus is associated with autoimmunity?
Expression of certain MHC alleles (D locus) confers higher susceptibility to loss of self tolerance
What is the genetic polymorphism is most commonly associated autoimmunity & RA?
- Encodes a tyrosine phosphatase
How do microbes precipitate autoimmunity?
Which gender is associated with higher incidence of autoimmunity? Why?
Female, which potentially suggests a role of sex hormones in autoimmunity
Generally, what balance is interrupted to cause autoimmunity?
Genetic background + enviornmental factors= autoimmunity
What is SLE?
Systemic Lupus Erythematous: prototypical multisystem autoimmune disorder
What gender is SLE more common in? What race?
African american females
What are the ACR diagnostic criteria for SLE?
1) Malar/ butterfly rash on face
2) Discoid rash--erythematous raised patches with adherent keratotic scaling & follicular plugging
4) Oral ulcers (painless)
6) Serositis--pleuritis or pericarditis documented by ST elevation in all leads (except aVR)
7) Renal disorder i.e. proteinuria/ casts
8) Neurologic disorder i.e. seizures or psychosis
9) Hematologic disorder i.e. hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia
10) Immunologic disorder
11) Antinuclear antibodies
Outline the pathogenesis of SLE.
- UV irradiation or other environmental insult results in apoptosis
- Inadequate clearance of these cells= high burden of nuclear antigens
- Underlying genetic defect e.g. HLA-DQ= defective self-tolerance
- Self-reactive lymphocytes remain active
- Activation of helper T-cells & B-cells that produce autoantibodies to nuclear antigens
What are the most common symptoms of SLE?
Chronic remitting & relapsing febrile illness, characterized by injury to the
- serosal membranes
****Note that 100% of SLE patients have hematologic conditions at some point
What are the hallmark autoantibodies associated with SLE?
Anti-nuclear antibodies; specifically, antibodies to DSDNA, or "SMITH ANTIGEN (SM)"
What is ANA testing?
Flourescent testing of antinuclear antibodies (ANA) i.e.
1) Antibodies to DNA
2) Anditbodies to histones
3) Antibodies to nonhistone proteins bound to RNA
4) Antibodies to nucleolar antigens
What is peripheral rim staining on fluorescent ANA testing indicative of?
Antibodies to dsDNA associated with active SLE
What is homogenous staining on fluorescent ANA testing associated with?
Indicates antihistone antibodies associated with:
- Drug induced SLE
What is speckled staining on fluorescent ANA testing associated with?
Indicates antibodies to non-DNA nuclear constituents & is the least specific ANA pattern. Associated with:
- Sjogren's Syndrome
- Systemic scleroisis
What is nucleolar staining on fluorescent ANA testing associated with?
Indicates antibodies to RNA, which is assocaited with:
- Systemic Sclerosis
What is the centromere staining pattern on fluorescent ANA testing associated with?
Indicates antibodies to centromeres.
****This is NOT associated with SLE, rather, systemic sclerosis & CREST
List the specific Lupus ANAs.
- Anti-ribonucleoprotein i.e. anti- Smith
- Antibodies to blood cells
- Antibodies complexed to phospholipids
What Hypersensitivity mechanisms underlie the symptoms of SLE?
- Type II is directed against blood cells & results in the frequent hematologic effects
- Type III mechanism causes visceral lesions
What percentage of SLE patients have arthralgia or arthritis? Why?
- 80-90% if patients have joint symptoms
****Caused by immune complex (Type III) deposition in the synovium
What does the malar/ butterfly rash spare?
What causes the malar rash associated with SLE?
Destruction of the epidermal/ dermal junction
What are the acute & chronic vascular changes associated with SLE?
Acute= vasculitis with fibrinoid necrosis of arteries & arterioles in any tissue
Chronic= layered fibrous thickening
****Note that these are caused by circulating immune complexes to ANAs that deposit in vascular beds & initiate a Type III reaction
What is "onion-skinning" ? What causes the "onion-skinning" associated with SLE?
"onion-skinning"= pathognomonic appearance of vascular lesions in SLE
- Smooth muscle cell proliferation
- Increased intercellular collagen
What is the major cause of morbidity & mortality of lupus?
Kidney failure from "lupus nephritis"
What is lupus nephritis?
This was the prototype immune complex glomerulonephritis
What is serositis?
Serosal effusions principally involving the pleura & pericardium
What cardiac complications are associated with SLE?
- Nonbacterial endocarditis
- Accelerated coronary artery disease
What are Libman Sacks disease?
Nonbacterial endocaritis affecting any valve, both sides of the valve, & usually the AV valves
How does lupus endocarditis compare to other forms of endocarditis?
RHD= Small, warty vegetations along lines of closure of valve leaflets
IE= Large, irregular destructive masses on valve cusps that extend into the chordae
NBTE= small bland vegetatons at the line of closure
LSE (SLE)= Small/ medium sized vegetations on either/ both sides of the valve leaflet
What happens to the lungs with SLE?
Pleuritis w/ effusion
Describe the pathology seen in the lungs of SLE patients with acute involvement.
Pneumonitis with alveolar damage, edema, & hemorrhage
Describe the pathology seen in the lungs of SLE patients with chronic involvement.
Interstitial & vascular fibrosis leading to pulmonary fibrosis & pulmonary HTN
What are the neurologic manifestations of SLE?
- Focal deficit
- Neuropsychiatric symptoms
What is the clinical course of SLE associated with?
Titers of autoantibodies
*****Note that the course of SLE is highly variable
What is discord lupus?
Skin only without systemic features
What is subacute cutaneous LE?
An intermediate between discord & SLE
What drugs can cause drug-induced lupus?