Rheumatic Heart Disease

Question 1

How does immune system maintain its unresponsiveness to self-antigens?

Answer 1

**Central Tolerance: ** developing lymphocytes undergo negative selection: if recognize self they undergo: apoptosis (cell death), change in receptors (receptor editing in B cells), or development of regulatory T lymphocytes (CD4+ T cells only)

Peripheral Tolerance: occurs when mature lymphocytes in peripheral tissues recognize self antigens. They undergo: anergy (unresponsiveness), apoptosis or suppression via T regulatory lymphocytes

Question 2

. Define anergy and describe the signals that result in induction of anergy. Contrast anergy to apoptosis.

Answer 2

Anergy: Lymphocytes are “disabled” and become functionally unresponsive. Low or Large amount of antigens and T cell becomes unresponsive to the antigens.

Apoptosis: Cell death

Question 3

Epitope spreading

Answer 3

Tissue damage and release of self-Ags. Build memory populations of self-reactive lymphocytes. Lymphocytes are further activated against self and tissue damage ensues, leading to more self-ags being released. Which leads to Bystander activation.

Question 4

2. Bystander reaction:

Answer 4

2. Bystander reaction: Nonspecific activation of self-reactive lymphocytes, resulting in inflammation and infiltration of tissue by self-reactive T cells. Complement fixation occurs which results in Ab’s binding self tissues, this response perpetuates and leads to cryptic antigens.

Question 5

3. Molecular mimicry

Answer 5

Molecular mimicry: Activation of cross-reactive Th1 cells that recognize both the microbial epitope and the self epitope. This activation results in release of cytokines and chemokines , which recruits macrophages. B cells are then activated against the self-antigen. Leads to epitope spreading.

Question 6

4. Cryptic antigen presentation

Answer 6

Cryptic antigen presentation: self Ags that have been taken up, processing in dendritic cells results in a way that selfAgs are not normally processed in bone marrow or thymus, self tissues are presented to b cells and T cells in a way that they have not seen before, thus the lymphocytes become reactive to self.

Question 7

Fertile field hypothesis

Answer 7

Fertile Field hypothesis: gender and genetics play a part in autoimmune diseases, as well as the timing of viral infections. First exposure to a pathogen: have normal response, but given age, gender and genetics results in an abnormal response and generation against self Ag’s due to molecular mimicry, cryptic Ag presentation etc.
When exposed to pathogen again: get the same response and results in further propagation of self Ags along with other viral Ags.

Question 8

What are the immunological responses that lead to the development of RHD?

Answer 8

Molecular Mimicry: M protein Ab’s produced to the cardio myosin, upregulation of adhesion molecules, brings in T cells macrophages, neutrophils, production of cytokines, more infilatration of lymphocytes. Ab are produced that find valvular endothetlial cells and basement membrane of the valves.

Epitope Spreading/ Bystander Activation: Neovascularization and recruitment of T cells

Cryptic Ag presentation: T cells respond to cardiac cells that have bound antigens.

Question 9

What are symptoms of actue rheumatic fever?

Answer 9

Inflammatory disease of heart, joints, subcutaneous tissues
Occurs between ages 5-15 y/o (priming event of fertile field hypothesis)
No predilection for gender
Previous sore throat 1-5 weeks prior to ARF (50% of schoolchildren are carriers – treatment of penicillin to prevent spread)

• polyarthritis
• carditis
• connective tissue problems: subcutaneous nodules, Erythema marginatum
• sydenham’s chorea

Question 10

what is the cause of the polyarthritis?

Answer 10

• Polyarthritis: primary symptom: cripping with associated fever – usually subsides within 4 weeks. Large amounts of WBC’s are found in synovial fluid – due to hyaluronic acid capsule of strep, resulting in WBC’s binding to hyaluronic acid capsule in our joints.

Question 11

What is the cause of the carditis?

Answer 11

• Carditis: presents 3 weeks post infection: cardiomegaly due to valve insufficiencies. Pancarditis, and rhythm disturbances – AV blocks. Diagnosed via pediatrician picking up new murmurs, usually apical systolic. Mitral valve usually has most insufficiency.
  M protein is virulence factor: mimics cardiac myosin, and only differs in about three basepairs. Ab production to cardiac myosin of heart and valves, does not cross-react with cardiac myosin in the valves.

Question 12

What is the cause of the connective tissue problems in acute rheumatic fever?

Answer 12

• Connective tissue problems:
• Subcutaneous nodules: painless, firm, nodules appearing on bone surfaces. Almost always in association with carditis
• EM: Migratory rash, that often accompanies carditis and subcutaneous nodules virulence factor of glacnac interacting with connective tissue carbohydrates

Question 13

What is sydehham’s chorea?

Answer 13

• Sydenham’s Chorea: “Chorea Dance” develops several months post infection. Results in rapid, purposeless, involuntary movments, generalized muscle weakness, emotional lability, disappears during sleep. Treated with sedatives and corticosteroids. Virulence factor is GlacNac crossreacting with neurons on caudate nucleus.

Question 14

What is Jones Criteria?

Answer 14

Jones Criteria: in order to diagnose ARF, must have two major manifestations and two minor manifestations along with IGG showing S. pyogenes infection

Major: Carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules

Minor: Arthralgia, gever, elevated ESR or CRP, EKG evidence of prolonged PR interval

Treated with Phenoxymethylpenicillin and sulphonamide: Have carditis must be treatd for 10 years or longer on this antibiotic regimen. No carditis, treats five years. Consider lifelong treatment if considered high risk

Question 15

What are the symptom’s presented in the case?

Answer 15

Symptoms presented in case: Systolic heart murmur and diastolic heart murmur (incompetence of mitral and aortic calves resulting in dilation of left atrium and ventricle),
Strep throat prior to disease,
Very high IgG (indicates second immune response, that he has had the infection before)
Very high anti-Streptolysin antibodies

Question 16

What is RHD? How does it happen? What do we see cardiac? Histo staining?

Answer 16

RHD:

• Must have had previous experience of ARF.
• Antibiotic prophylaxis did not occur, usually see recurrent attacks in a ten year period (fertile field hypothesis).
• Start getting periarticular fibrosis in joints because of connective tissue involvement with hyaluronic acid capsule.
• Residual cardiac involvement: Atrial Fib, scarring of valves, stenosis. Valve replacement is common and usually the only way to treat.
• Histologically the cardiac tissue would see chordae are shortened, fissures are fused and edges of valve are thickened. Would see Aschoff’s Nodules: perivascular inflammatory lesions containing lymphocytes, plasma cells and Aschoff cells (large basophilic multinucleate cells). Will also see Anichkov’s myocytes (elongated nuclei distinctive chromatin pattern)