ABO/Rh Multiple Myeloma - Schein 4/7/16 Flashcards Preview

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Flashcards in ABO/Rh Multiple Myeloma - Schein 4/7/16 Deck (22):
1

[unrelated material - need to know!]

 

cytokines in Th1 and Th2 devpt

Th1 : IL2, IFNgamma → activates macrophages

Th2 : IL4, IL10 → help B cells produce antibody

2

[unrelated material - need to know!]

 

tuberculoid leprosy

vs

lepromatous leprosy

 

tuberculoid leprosy

characterized by relatively good control of the M. leprae by Th1 activation of infected macrophages → granuloma formation, local infl

 

lepromatous leprosy

Th2 response → antibody response

  • ineffective against intracellular pathogen

3

composition of the blood

formed elements

  • RBCs (erythrocytes)
  • WBCs (leukocytes)
  • platelets

plasma

  • albumin
  • antibodies
  • complement
  • clotting factors
  • acute phase proteins
  • etc

 

*plasma - (clot formed when activating clotting factors) = SERUM!

4

blood group antigens

terminal carbohydrate moieties on large glycoprotein/glycolipids on cell membranes

  • core glycan + terminal sugar
  • approx 2M on each RBC membrane

5

glycosyltransferase

chr9 : glycosylase gene (3 alleles(

adds terminal sugars onto core carb that's already on blood cells

  • + GalNAC = type A
  • + galactose = type B
  • + nothing = type O

 

in general:

h antigen + fucosyl [fucosyltransfersase] → H antigen + terminal sugar [glycosyltransferase] → ABO blood

  • sets you up with the RBC antigen (H, A, B, AB) specific for your blood type (O, A, B, AB)

6

antibodies against blood antigens

"natural antibodies"

 

blood antigens are glycolipids (sugar moieties)

  • T-indep antibodies are produced
  • usually IgM subtype (do not type-switch)
  • preformed and "opposite" to the blood type that you have...WHY/HOW?
    • antibodies produced against glycolipids expressed by gut bacteria!

bc antibodies against other blood types exist...

  • transfusion of wrong blood type → severe rxn (Type II hypersensitivity)

7

special case:

Bombay O!

typically: h → H → A/B/O

in Bombay O, no h → H conversion takes place [no fucosyltransferase]

  • people appear to be type O on blood test, but with important diff in antibody production...
  • make anti-A, anti-B, and also anti-H antibodies → react with normal O blood! (nothing else does)
    • recog'd by agglutination of type O with anti-H

8

blood transfusion rules

whether transfusion rxn occurs depends on...

  • what you transfuse
  • volume transfused
  • whether transfusion occuring is routine or emergent
    • O- RBCs ONLY  can used in emergency situations (antigen-less)

don't want cross-rxn between antigens/antibodies, so need to consider:

  • recipient RBC antigens [ex. A]
  • recipient plasma antibodies [ex. anti-B]
  • what blood type doesn't contain antigen/antibodies that would cross-react

9

what to consider in diff types of blood transfusions (whole vs. RBC vs. plasma)

whole blood transfusion [consider donor antigens&antibodies]

vs.

RBC transfusion [consider donor antigens only]

vs. 

plasma transfusion [consider donor antibodies only]

10

transfusion reaction

 

primary rxn

mop up rxn

2 additional rxns

anti-ABO antibodies coat the RBCs they recognize as foreign

 

primary rxn : intravascular hemolysis via complement rxn [type II rxn]

  • anti-ABO antigens are IgM → excellent at activating complement

to a lesser degree : RBCs opsonized with antibody and/or complement can be phagocytosed by macrophages in liver/spleen 

 

cytokines released in large quantities → CYTOKINE STORM, activation of whole immune system

possible disseminated intravascular coagulation (DIC)

  • localized clotting in circulation
    • cuts off organ blood supply
    • sequesters clotting factor supply → bleed out even with DIC in effect 

 

11

Rh factor

 

  • what is it
  • antibodies?

non-glycosylated RBC cell surface protein 

  • many genes, of which one is medically important: Rh0D gene (15% of the pop has a deletion, making them Rh-)

 

BODY WILL NOT MAKE NATURAL ANTIBODIES TO IT! → will make IgG antibodies on exposure [IgG because protein]

  • IgG can cross placental barrier (IgM cannot...)
    • explains why mom/child situation can arise with Rh mismatch, but not with ABO mismatch!
  • IgG does not activate complement well, but does opsonize RBCs for phagocytosis in spleen

12

Rh Incompatibility Disease

important in the fetus...

  • erythroblastosis fetalis
  • hemolytic disease of the newborn
  • hydrops fetalis

 

Rh- moms can be sensitized by blood that enters their circ during birth of an Rh+ child

  • moms have immune response, which is retriggered by the next Rh+ child in utero
  • mom's now-extant IgG can cross the placental barrier → fetal hemolysis :(

tx

  • blood type parents
  • give rhogam (anti-Rh antibodies during 3rd trimester, within 72 hours of birth) → suppresses mom from making anti-Rh antibodies!
    • kill fetal cells that get into mom's circ BEFORE they can trigger an immune response!
    • Ab feedback → presence of anti-Rh will suppress MOM'S synthesis of anti-Rh through her own immune response
  • cytokines interrupt antigen-specific B cells from becoming plasma cells
  • ABO incompatibility can also have a "protective" effect → kill baby's cells that enter mom's circ before she becomes sensitized to the Rh and starts pumping out the antibodies!

13

compare and contrast:

 

anti-ABO

vs

anti-Rh

anti-ABO - IgM

  • have abundant Ag to bind to
  • activate complement well
  • destroy RBC in bloodstream, primarily by complement rxn
    • intravascular hemolysis

anti-Rh - IgG

  • have ltd Ag to bind to
  • don't activate complement well
  • destroy antibody-opsonized RBC in liver and spleen via macrophage phagocytosis
    • extravascular hemolysis

14

other minor blood groups

similar to Rh...

  • require exposure for antibody response (not natural; not preformed)
  • trigger IgG production
  • make up low proportion of proteins on RBCs
  • hemolytic disease of newborn is possible...but not likely at all

15

IgM

IgG

IgA

 

antibodies!

IgM - pentamers

  • easy for them to agglutinate RBCs (can hold on to several at once, binding the antigens which are all over the place) → form lattice

IgG - monomer

  • small, don't agglutinate well (and have sparse antigen to hang on to...and RBCs have a net neg charge which makes them tricky to get close together anyway) → need fixes to get around these barriers

 

IgMs are big enough to bridge zone of repulsion, but IgGs are not → use solutes that neutralize RBC charge and/or increase cell crowding with IgG!

 

IgA - dimer

 

 

16

Coombs' Test

(Antiglobulin Test)

 

two forms: direct and indirect

direct Coombs' test

  • detects cell-bound antibodies
  • positive: indicative of some kind of autoimmune hemolytic rxn

patient RBC + Coombs' reagent( rabbit anti-humanIgG)

indirect Coombs' test

  • detects anti-Rh (aka anti-D) IgG in plasma
  • positive: detects sensitization of Rh- mom to current/future Rh+ kid

patient plasma + donor RBC [or RBC with whatever you want to check reactivity with] + Coombs reagent

17

multiple myeloma

malignancy of antibody-producing plasma cells

  • most common lymphoid malignancy (20k new cases annually, median age 70)

 

multiple bc by time of detection, there are usually multiple foci - many clumps of tumor cells

myeloma bc tumors form in bone marrow (where most normal plasma cells are) → erodes bone via stimulation of osteoclasts

 

KEY CHARACTERISTIC

osteoclasts often activated → coin lesions

immunosuppression : despite pumping out extra antibodies, overproduction of one might be leading to underproduction of another isotype → can't mount approp immune response → recurrent infections

 

 

18

serum electrophoresis

 

 

blood protein profile

  • peaks for albumin, alpha1, alpha2, beta, GAMMA (contains antibodies aka gamma-globulins)
  • myeloma = "gammopathy" bc antibodies are in the gamma section

narrow peak : 1 or small number of proteins

broad peak : large number of proteins within that group

19

why is multiple myeloma aka monoclonal gammopathy?

monoclonal : plasma cell tumors with uncontrolled prolif of one cell type → overproducing one isotype of antibody

  • secreted antibody aka paraprotein or M protein

gammopathy : antibodies aka gamma-globulins are found within the gamma peak in serum electrophoresis

20

monoclonal gammopathies

  • multiple myeloma [own flashcard]
  • Waldenstrom's macroglobulinemia

Waldenstrom's

  • less mature B cells → secretes IgM
  • big molecules! → viscous blood
  • less bone marrow involvement

heavy chain disease

  • only heavy chain secreted

light chain disease

  • only light chain secreted
  • light chains in urine = Bence-Jones proteins

21

serum electrophoresis results in multiple myeloma

will see a large increase in gamma region!

aka "M spike" = myeloma spike

  • serum electrophoresis WILL NOT TELL YOU WHICH ISOTYPE IS ELEVATED

monoclonal : will see a realtively thin gamma peak (bc one type that's being overprolif'd)

polyclonal : will see a broader peak

22

how do you figure out which Ig is elevated in multiple myeloma???

immunofixation : separate proteins, add anti-Ig antibodies

  • see which antibodies bind!
  • multiple myelomas should have 1 light chain (kappa, lambda) and 1 heavy chain (G, M, A) being overrepresented