BL.2.4: Type 2 Immunopathology, Platelet disorders Flashcards

1
Q

Describe the molecular and cellular details of the immunologic mechanisms by which tissue damage occurs in a Type II reaction.

A

aka Cytotoxic antibody” reactionsSelf reactive antibodies attack your own tissue

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2
Q

Give an example of a Type II mechanism disease of muscle, kidney, heart, red cells, platelets, lung, thyroid, pancreatic islets.

A

Muscle:Myasthenia gravis: progressive muscle weakness. Ab to myosin and Ach receptorKidney: Goodpasture’s diseaseHeart: Rheumatic heart disease, from strep A cross reactivityRed cells: AIHAPlatelets: Autoimmune thrombocytopenic purpura (say that 3x fast). Platelets opsonized rapidly in spleen.Lung: Goodpasture’s diseaseThyroid: Grave’s disease, Hashimoto’sPancreatic islets: Diabetes

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3
Q

Describe the fluorescent antibody tests which would allow you to make the diagnosis of Goodpasture’s Syndrome, given: patient’s kidney biopsy, normal kidney biopsy, patient’s serum, and fluoresceinated goat antisera to human IgG and complement.

A

In Goodpasture’s the antibody is directed against the basement membrane, not trapped as clumps, so the staining by immunofluorescence is sharp and ‘linear,’ not ‘lumpy-bumpy’ as it is in Type III, immune complex conditions.Kidney biopsy: patient’s basement membrane would be ravaged by immune system, and evidence of glomerulonephritisThey would also have a glowing serum because the goat antisera would bind this person’s IgG and complement.

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4
Q

Distinguish between the “lumpy-bumpy” and “linear” immunofluorescent patterns in terms of the most probable immunopathologies they represent.

A

Type 2: sharp and linearType 3: lumpy bumpy

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5
Q

Describe how you could tell, using fluorescent antibodies and biopsies of patient’s kidney, if Type II or Type III immunopathology was involved. Name the antibodies you would use and the fluorescent patterns you would see.

A

Is it lumpy bumpy or is it sharp and linear??Lumpy bumpy = 3, Sharp linear = 2Were I looking for Goodpasture’s (Type 2), I would use anti-anti-basement membrane IgG tagged with pink sparkles and get sharp, linear, pink sparkles on the basement membrane of my kidney sample.If I was searching for a type 3 result, I would look for lumpy bumpy glowing immune complexes stuck in the kidney.

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6
Q

Given patient’s serum, fluorescent antibody to human immunoglobulins, and slices of normal kidney, describe how you could tell if the patient’s glomerulonephritis was due to Goodpasture’s disease or SLE.

A

Lupus: Check serum for antibodies for Nuclear proteins, DNA, RNA, erythrocytes, clotting factors, platelets, skin and T cells. If they have this, and large immune complexes have formed, they will have gotten stuck in the kidney. Apply the fluorescent antibody to the kidney, and observe a lumpy bumpy pattern.Goodpastures: is there a linear glowing pattern on the basement membrane?

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7
Q

Describe how antibody-mediated tissue damage could result from: The innocent bystander phenomenon.

A

Innocent bystander. A common mechanism, in which there is damage to normal tissue which happens to be associated with or infected by the antigen, which is truly foreign. Usually this is a result of the T cells calling in angry macrophages which end up damaging the regular tissue as an innocent bystander.

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8
Q

Describe how antibody-mediated tissue damage could result from: Cross-reaction of a foreign antigen with self.

A

Could be the case in Type 1 diabetes. Many patients are sick with a virus before diagnosis. The foreign antigen may look like an islet cell, and then the immune system goes after them!

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9
Q

Describe how antibody-mediated tissue damage could result from: Coupling self antigen with a foreign antigenic “carrier”.

A

Suppose you had anti-self B cells that hadn’t been aborted. They would not necessarily get you into trouble if the self antigens were T-dependent, and you did not have antiself T helper cells. Suppose that a foreign antigen were to couple to the self antigen. The anti-self B cell could bind and ingest self, and carry the foreign antigen along with it. Then foreign epitopes might be presented to a helper T cell on the B cell’s Class II MHC. The B cell would have received both necessary signals (from its receptor and from the T cell) and become activated.

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10
Q

Describe how antibody-mediated tissue damage could result from exposure of a sequestered antigen.

A

Note that in the special case of sequestered antigens, the antigen cannot get out into the general system, and therefore is not normally immunogenic.But if an immune response does get initiated, then the response can usually get into the place where the antigen was sequestered.Example: some men who get mumps end up sterile. It is thought that the mumps breaks down the blood/testis barrier, allowing immunization to sperm antigens.

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11
Q

Describe how antibody-mediated tissue damage could result from inadequacy of Treg cells.

A

A proper balance between Th1, Th2, and Treg activity usually assures that immune responses are appropriate.However, if that balance is perturbed one can imagine that too many Th1 cells might be stimulated, calling their friends, the angry macrophages. Those cats can’t be turned off → the tissue could easily be damaged in this situation.

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12
Q

Identify “Rheumatoid Factor” and describe its molecular nature.

A

IgM anti IgG

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13
Q

Name a condition in which antibody stimulates rather than inhibits or harms its target cell.

A

Grave’s disease.

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14
Q

Discuss how the Aire gene is involved in preventing autoimmune disease.

A

Amazingly, the Aire (autoimmune regulator) gene causes thymic stromal cells to express a wide variety of otherwise-inexplicable “out-of-place” peptides so that reactive T cells may be removed from the repertoire.In fact, Aire-deficient people develop multiple autoimmunities.

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15
Q

Discuss the idea that switching from Th1 to Th2 or Treg responses may be a way to treat autoimmune disease.

A

Remember that a proper balance between Th1, Th2, and Treg activity usually assures that immune responses are appropriate.Such balance is an area of intense speculation lately.Some recent experiments that cause major shifts in T cell balance look very promising as therapy, if they can make the translational jump from the lab or the Phase I trial into safe general use.

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16
Q

Review events occuring during hemostasis. Compare primary and secondary hemostasis.

A

Hemostasis overall: Vascular phase, platelet phase, coagulation phase, regulation of clot, remodeling and repair.Adhesion, activation, and aggregation of platelets to form a platelet plug constitute the first events in formation of a clot (primary hemostasis). The platelet plug is stabilized by formation of a fibrin network generated through the coagulation cascade (secondary hemostasis).

17
Q

List three functions of platelets.

A

Platelets play several important roles in hemostasis including: adhesion to the vascular subendothelium at sites of injury to begin the hemostatic process activation of intracellular signaling pathways leading to cytoskeletal changes and release of intracellular granules to enhance platelet plug formationaggregation to form the platelet plug, and support of thrombin generation by providing a phospholipid surface for the coagulation cascade to take place

18
Q

Construct a simple diagram that depicts the process of platelet adhesion. Include in the drawing subendothelial collagen, von Willebrand factor, and glycoprotein Ib.Explain why platelet adhesion to blood vessels does not occur under normal circumstances.

A

With vessel injury, subendothelial components are exposed. Circulating von Willebrand factor (vWF) adheres to the damaged, exposed subendothelium. Under conditions of high shear flow, circulating platelets then contact the exposed subendothelium in a rolling fashion and adhere by interaction between glycoprotein Ib (GP1b)on the platelet surface and vWF. With exposure to soluble agonists such as thrombin, ADP, epinephrine, and thromboxane A2, or to adhesive proteins in the subendothelial matrix such as collagen and vWF, the platelet integrin GPIIb- â€êIIIa (αIIbβ3) increases its affinity for vWF, leading to tighter binding.The endothelial cells of intact vessels prevent blood coagulation by secretion of a heparin- â€ê like molecule and through expression of thrombomodulin, which when bound to thrombin activates protein C and S. Intact endothelial cells prevent platelet aggregation by the secretion of nitric oxide and prostacyclin, inhibitors of platelet activation.

19
Q

Similarly, construct a simple diagram that shows the process of platelet aggregation; include the release reaction (ADP), thromboxane synthesis, ADP and thromboxane receptors, glycoprotein IIb/IIIa, and fibrinogen.

A

After adherence, the contents of platelet granules are released. Soluble agonists, including thrombin, thromboxane A2, epinephrine, and ADP, interact with their respective G protein coupled platelet membrane receptors, leading to intracellular signaling and calcium mobilization. Calcium activates phospholipase A2, which releases arachidonic acid from phospholipids. Cyclooxygenase (COX-­â€ê1) then converts arachidonic acid to prostaglandin H2, which in turn is converted to thromboxane A2 by thromboxane synthetase. Thromboxane A2, along with other agonists, is released, acting to further amplify platelet activation. With platelet activation, membrane reorganization also occurs, with switching of the phospholipid phosphatidylserine from the inner to the outer membrane leaflet, making it available to interact with clotting factors that then lead to thrombin generation.

20
Q

List and describe three mechanisms that could lead to thrombocytopenia.(not pseudothrombocytopenia - the photo -Those are from platelet clumps, silly goose.)

A

ïÅ® Decreased production of platelets: bone marrow failure, nutritional deficiencies, EtOH, malignancies, drug induced, radiation, and viral infections (HIV, hepC)ïÅ® Increased destruction of platelets: rapid process, bone marrow can’t keep up. Immune thrombocytopenia (most common), DIC (rare), sepsis (rare), Thrombotic Thrombocytopenic Purpura (rare)ïÅ® Distribution/Dilution disorders (Increased sequestration of platelets due to splenomegaly)

21
Q

Identify three methods of treating Immune Thrombocytopenia (ITP) and the mechanism by which they increase the platelet count.

A

Steroids: dampen B cell clone making autoantibody, takes 7-10 daysIVIG: acts by blocking splenic Fc receptors and takes 1-2 days to start workingSplenectomy: removes site of autoantibody induced platelet removal via Fc receptors of splenic macrophages

22
Q

Describe the molecular defect, typical clinical course, and general approach to treatment for a patient with Von Willebrand Disease.

A

Autosomal dominant/recessive. 3 Types.2 have qualitative and 1 has quantitative defects in vWF which causes abnormality in platelet/endothelial interaction, also is a carrier for factor VIII, a protein with a very short half lifeType 1: 70-80% cases. Partial quantitative deficiency.Type 2: 15-30 cases. Qualitative. Decreased adhesion to platelets.Type 3: Rare. Near complete absence of vWF.Mucosal bleeds, nose bleeds, GI bleeds, Menorrhagia, bleeding after surgeryDon’t take anti-platelet agents (aspirin, NSAIDs), can take DDAVP for type 1 (quantitative) which enhances release of vWF from endothelia, rarely long term prophylaxis

23
Q

List important questions to ask when obtaining a bleeding history in a patient with excessive bleeding.

A

ïÅ® Excessive, prolonged, recurrent, or delayed bleeding?ïÅ® Abnormal bruising or petechiae?ïÅ® Nosebleeds or menorrhagia vs. soft tissue or joint hemorrhage?ïÅ® Hematemesis, melena, hematuria, hemoptysis without obvious cause?ïÅ® Prolonged or recurrent bleeding after laceration, surgery, tooth extraction, or childbirth?History and severity of symptoms, prior stressers, family history, drugs, previous coagulation, concurrent illnesses.

24
Q

List important laboratory studies to obtain when evaluating a patient with excessive bleeding.

A

CBC, smearPlatelet count and smearPlatelet function analyzerBleeding time (not very common anymore)PT/INRaPTTThrombin Time (TT)Fibrinogen level