FMS Week 10 Flashcards
Immunology
What is graft-vs-leukemia effect?
T-cells from donated bone marrow have mild GVHD and kill residual cancer cells
How are PABs and MABs used in organ transplantation?
At the beginning, to suppress the immune system for a “clean start” or in crisis
Why does glucocorticoids cause increased WBC counts?
impaired neutrophil migration
What genes are important for MHCI matching?
HLA-A, HLA-B, HLA-C of chromosome 6
Features, symptoms, findings, and treatment of Leukocyte Adhesion Deficiency:
Defective neutrophil/lymphocyte migration
Type 1: defect in CD18 (LFA1) which is part of several integrins
Key findings: delayed umbilical separation, omphalitis (stump infection), recurrent bacterial infections, elevated WBC (especially neutrophilia)
What are TRECs?
Loops of DNA that are formed during recombination of TCR; presence indicates that SCID is unlikely in neonatal testing
What are the advantages of virus-like particle vaccines?
Very safe, do not need to grow pathogen, highly immunogenic, inside of particle can be modified with adjuvants
What is the primary target of HIV?
CD4 Th cells
What is the most common presentation of chronic rejection in the heart?
narrowing of coronary arteries
Where are H1 receptors most common?
Endothelial cells and sensory nerve endings
also GI/bronchial smooth muscle and brain
what is a xenograft?
transplant taken from another species
Why are steroids usually tapered down?
Can lead to adrenal insufficiency, steroid use suppresses HPA axis
Adrenal crisis: hypotension/shock, weakness, fever, confusion/coma, abdominal symptoms
What are the disadvantages of DNA vaccines?
effectiveness unclear (may be more effective in therapeutic vaccines), safety unclear, likely multiple doses/delivery platforms
What autoimmune diseases are associated with HLA-B27?
ankylosing spondylitis, psoriasis, IBD, Reiter syndrome
Who are most at risk of hyperacute rejection?
parrous women, people having received blood transfusions or previous transplants
Mechanisms, presentation, key findings and treatment of X-linked Agammaglobulinemia:
(Bruton Agammaglobulinemia) Defect in bruton tyrosine kinase gene (BTK); light chains of b-cells not produced
Symptoms begin around 6 months of age after loss of maternal antibodies
Recurrent respiratory bacterial infections (loss of opsonization): recurrent otitis media/sinusitis/pneumonia
GI pathogen infections (loss of IgA): enteroviruses &
giardia
Key findings: absence of mature peripheral B cells and antibodies, underdeveloped germinal centers of lymph nodes
Treatment: IVIG (intravenous immunoglobulin)
What is the most common organ transplant?
Kidney (you only need one)
What are the most important eicosanoids for protecting GI mucosa?
PGE2 and PGI2
what are the disadvantages of live attenuated vaccines?
can revert back to pathogenic form, requires system to grow virus, potential contamination, less safe
What is a syngenetic graft?
transplant taken from identical twin
What is the presentation of hyperacute rejection?
blood vessels spasm leading to intravascular coagulation and ischemia (white rejection)
What are the 3 main genes of HIV?
Gag (nucleocapsid)
Pol (polymerase)
Env (envelope proteins)
COX-1
constitutively expressed cyclooxygenase in all cells
important for GI mucosal function
Features, symptoms, findings, and treatment of ataxia telangiectasia:
Defective ATM gene on Chromosome 11 (dsDNA repair, nonhomologous end-joining)
Autosomal recessive; hypersensitivity of DNA to ionizing radiation
Symptoms: ataxia, spider veins, recurrent respiratory infections, high risk of cancer
Presents in childhood with progressive symptoms
Key findings: elevated AFP, low IgA
What is NF-KB
A key inflammatory transcription factor
Mediates response to TNF-alpha, controls synthesis of COX-2, PLA2, Lipoxygenase
Inactivated by glucocorticoids
Describe Avascular Necrosis:
Bone collapse, most commonly at the femoral head (probably from bone ischemia, thinning/demineralization, collapse)
Associated with long term steroid use; also with Lupus, sickle cell, alcoholism, trauma
What are the classes of anti-retroviral drugs?
entry inhibitors, RT inhibitors, Integrase inhibitors, protease inhibitors
Side effects of glucocorticoid use?
thin skin, easy bruising, Cushingoid appearance, osteporosis, Hyperglycemia, cataracts, myopathy, gastritis
What are the features of a good donor-recipient match?
same blood type, similar MHCs, negative cross-matching screen
What are MiHA?
minor histocompatibility antigens; polymorphic non-HLA proteins that are expressed by donated tissue that recipient T-cells have not been trained to tolerate
What autoimmune diseases are associated with HLA-A3?
hemochromatosis
What are the symptoms of graft vs host?
rash; GI:diarrhea, abdominal pain, inflammation; liver: elevated LFTs & Bilirubin
Features, symptoms, findings, testing, and treatment of SCID:
Loss of cell-mediated and humoral immunity (primarily T-CELL, secondary B-cell/antibody)
Most commonly X-linked (cytokine receptor gamma-c deficiency; especially IL-7 and IL-2); also caused by adenosine deaminase deficiency (decreased DNA synthesis)
Key findings: loss of T/B-Cell areas (thymic shadow & germinal centers)
Symptoms: Thrush, diaper rash, failure to thrive, other infections
Treatment: death w/o bone marrow transplant
Describe acute rejection:
Weeks/months after transplant; caused by infiltrating lymphocytes/monocytes; treatable with immunosuppresion
Features, symptoms, findings, and treatment of Thymic Aplasia:
DiGeorge (22q): failure of 3rd/4th pharyngeal pouches, usually de novo
Classic Triad: loss of thymus (T-cells, infections) loss of parathyroids (hypocalcemia, tetany), conotruncal heart defects (also palate defects)
Key findings: no thymus shadow on X-ray, low T-cell, underdeveloped T-cell structures
Treatment: thymic transplatation, hematopoietic cell transplantation
What are the advantages of DNA vaccines?
inexpensive, highly stable, quick development time
What type of allorecognition is involved in acute rejection?
direct (APCs from transplant activate recipient immune response)
What is the difference between direct, indirect, and semi-direct allorecognition?
Direct involves donor APCs presenting to recipient T-cells
Indirect involves recipient APCs collecting and presenting donated antigens
Semi-direct involves recipient APCs taking on MHC molecules from donor cell membranes
Features, symptoms, findings, and treatment of Chronic mucocutaneous candidiasis:
Defect in AIRE genes: Defective Dectin-1 (candida antigen response receptor), also endocrine autoimmunity (T-CELL)
Key findings: recurrent thrush, skin, and esophagus candida infections; hypoparathyroidism, adrenal failure; lack of candidemia (normal neutrophil defense)
What are the odds of a sibling being a perfect HLA match?
25% (genes are transferred en block from father and mother to offspring)
What are the 3 stages of HIV infection?
Acute, clinical latency, AIDS
What are the disadvantages of subunit vaccines?
often poorly immunogenic without adjuvants, polysaccharide antigens elicit T-independent responses
What are the advantages of inactivated vaccines?
no reversion, multiple antigens present
What are the adverse effects of traditional NSAIDs?
decreased platelet aggregation, decreased renal blood flow, decreased GI mucosa, intersititial nephritis
What are the advantages of live attenuated vaccines?
highly immunogenic (broad innate and adaptive response), multiple target antigens, single dose, inexpensive
What are the most important HLA genes for solid organ transplants?
HLA-A, HLA-B, HLA-DR
What are the key enzymes associated with HIV?
Reverse transcriptase, Aspartate protease (cleaves proteins), Integrase (integrates DNA into host cell)
What is the reason for kidney damage by NSAIDs?
Decreased renal vasodilation due to decreased PGE2
what are the disadvantages of virus-like particle vaccines?
may require multiple doses, limited immune response (only surface antigens), can be expensive
What type of allorecognition is associated with chronic rejection?
indirect (antigens from transplant are being taken up by recipient APCs)
Describe function of glucocorticoids:
diffuse across cell membranes (steroids), bind to glucocorticoid receptor, GR-steroid complex moves to nucleus where it alters gene expression
one mechanism is through inactivation of NF-KB
Features, symptoms, findings, and treatment of Hyper-IgM syndrome:
Class-switching disorder (only IgM): Usually defective CD40L on T-Cells (Type 1) also CD40 (type 3), both x-linked; also from defective AID (activation-induced deaminase, type 2, autosomal)
Symptoms: recurrent bacterial infections (encapsulated; no IgG opsonization)
Treatment: CD40 defects by HC transplant and AID with IVIG & antibiotic prophylaxis
what is an allograft?
a transplant taken from the same species
What are the 3 basic categories of immunosuppressive drugs?
Anti-inflammatory, T-cell activation signalling inhibition, cytotoxic (DNA replication interference)
Where are H4 receptors most common?
eosinophils, neutrophils, CD4 T Cells
What is the most common presentation of chronic rejection in kidneys?
fibrosis of capillaries and glomeruli
What are the regulatory genes of HIV?
Tat (transcription activator)
Rev (mRNA transport to cytoplasm)
Describe the capsid of HIV
multiple copies of p24 protein (non variable, not neutralized by antibodies)
What is graft versus host disease?
opposite of rejection; donor T-cells attack recipient cells; typically in bone marrow transplants
what are the disadvantages of inactivated vaccines?
risk of incomplete inactivation, system to grow virus, requires handling of virulent pathogen, expensive, requires boosting
Describe the envelope of HIV
phospholipid membrane from human cells; contains env protein
Important glycoproteins:
gp120 (attachment to T-cells)
gp41 (fusion and entry)
Both are cleaved from gp160
What is an autograft?
donor and recipient of transplant are the same person
What are the advantages of conjugated vaccines?
T-dependent response, most effective in children (strong IgG memory response)
What is Cushingoid appearance?
truncal obesity, buffalo hump, moon face, thin skin
due to excessive use to glucocorticoids
Describe hyperacute rejection:
within minutes of transplant; caused by preexisting antibodies in recipient to ABO or HLA antigens; treatable with cross-matching screening
What type of primary immunodeficiency is most common?
antibody/B cell deficiencies (65%)
COX-2
Inducible cyclooxygenase
mostly in inflammatory cells
What is the most common presentation of chronic rejection in lungs?
bronchiolitis obliterans
What are the tropes of HIV?
Receptors used to enter cells
CCR5 (early after infection, Tmemory/macrophages)
CXCR4 (occurs later, in T-cells)
What is the significance of C4d in transplant rejection?
C4d is a product of compliment activation, which suggests antibody response to transplanted tissue
What are the advantages of subunit vaccines?
specific immune responses against molecules involved in virulence/pathogenesis
What is the typical mechanism of vaccines against extracellular bacteria?
anti body production (neutralization and/or lysis)
Features, symptoms, findings, and treatment of chronic granulomatous disease:
Loss of function of NADPH Oxidase (cannot generate H202 for respiratory burst)
Cannot breakdown catalase positive bacteria and fungi: leads to recurrent infections of staph aureus, pseudomonas, serratia, nocardia, aspergillus (chronic T-cell stimulation and granulomas)
Testing: negative Nitroblue tetazolium test (stains NADPH oxidase in neutrophils blue)
Treatment: Lifelong antibiotic prophylaxis, early diagnosis, aggressive management (40yo prognosis)
What are alloantigens?
HLA mismatches
Adverse effects of COX-2 Inhibitors
Increase risk of MI and stroke; sulfa drugs
What are the types of NSAIDs?
Traditional: ibuprofen, naproxen, indomethacin, ketorolac, diclofenac
COX2 inh: celecoxib
Irreversible: Aspirin (anti-platelet)
Features, symptoms, findings, and treatment of Chediak-Higashi Syndrome:
Falure of lysosomes to fuse with phagosomes (microtubule dysfunction from CHS1/LYST gene)
Symptoms: recurrent bacterial infections (staph and strep), severe neuro impairment
Key findings: oculocutaneous albinism, coagulation defects
Treatment: HC transplant, prophylactic antibiotics
Prognosis: 7y life w/o transplant; but usually debilitating neuro deficits by 20yo
What are RAG1 and RAG2?
Proteins associated in VDJ recombination
Benefits of COX-2 inhibitors
Less risk of GI ulcers/bleeding
Features, symptoms, findings, and treatment of Wiskott-Aldrich Syndrome:
X-linked disorder of WAS gene: dysfunctional T-Cell cytoskeleton/immunologic synapse (cannot react to APCs)
Worsens with age, appears at 6mo
Key findings: immune dysfunction, low platelets, eczema, elevated IgE/IgA
Treatment: Bone marrow transplant, prophylactic antibiotics, platelet transfusions
Features, symptoms, findings, and treatment of Hyper-IgE syndrome:
AKA Job Syndrome, rare, immune symptoms with skin/bone findings
Defective Th17 (consequently no IL-17); loss of attraction of otherwise normal neutrophils; defects in STAT3 signalling pathway
Key findings: elevated IgE, low IFN-gamma
rash/eczema in first few weeks of life, “cold” abscesses of face/scalp
otitis, sinusitis, facial deformities, retained primary teeth
Why is it difficult to create antibodies to gp120?
it is highly variable and mutates rapidly
Features, symptoms, findings, and treatment of CVID:
common variable immunodeficiency: defective B-cell maturation, loss of plasma cells and antibodies; varying genetic causes
Findings: normal B cell count; absence of IgG (sometimes IgA/IgM)
Symptoms similar to X-linked Agammaglobulinemia: respiratory bacterial infections, enteroviruses/giardiasis
DIFFERENCES: Not X-linked, later onset (20-45yo)
Common along w/ RA, pernicious anemia, lymphoma
Treatment: IVIG to replace low Ig
Features, symptoms, findings, and treatment of Selective IgA Deficiency:
very common (1 in 600); defective IgA B-Cells; mostly asymptomatic
Symptoms: recurrent otitis media/sinusitus/PNA, giardiasis
Blood transfusions may lead to anaphylaxis due to anti-IgA antibodies; Commonly along with lupus and rheumatoid arthritis; may have false positive beta-HCG pregnancy test
Key findings: serum IgA <7mg/dl; normal IgG/IgM
Treatment: prophylactic antibiotics, IVIG (compensates w/ extra IgG/IgM)
Describe Acute Interstitial Nephritis:
unknown type of hypersensitivity reaction; usually triggered by drugs (NSAIDs)
not a disease of the nephron itself; classic finding is urine eosinophils
days to weeks after exposure: fever, rash, oliguria, +BUN/Cr
Why do MHCII molecules also need to match in transplants?
some donor APCs may be carried in tissue; also vascular endothelial cells may express MHCII
What is the typical mechanism of vaccines against intracellular bacteria?
cytotoxic lymphocytes; though there are not really effective vaccines of this type that are approved
Describe chronic rejection:
months/years after transplant; occurs in most transplants; inflammation and fibrosis, especially of vessels; involves cell-mediated and humoral immunity
What genes are important for MHCII matching?
HLA-DM, HLA-DO, HLA-DP, HLA-DQ, HLA-DR of chromosome 6
What are the primary markers for HIV infection?
Low CD4 T-cell count, viral load (amt of HIV RNA)
