Exam #3: Immuopathology II Flashcards Preview

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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?

PTPN-22 gene
- Encodes a tyrosine phosphatase


How do microbes precipitate autoimmunity?

Antigenic mimicry


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
3) Photosensitivity
4) Oral ulcers (painless)
5) Arthritis
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
- skin
- joints
- kidney
- 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:
- RA
- 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-dsDNA
- 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?

Nasolablial fold


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?

- Pericarditis
- Myocarditis
- 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
- Seizures
- 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?

- D-penicillamine
- Procaianamide
- Hydralazine
- Isoniazid


What symptoms differentiate drug induced & SLE?

NO renal or CNS pathology