Immunology
Describe the response of macrophages to Gram negative bacteria
Gram negative bacteria possess lipopolysaccharides (LPS). LBP (LPS-binding protein) binds LPS and presents it to CD14 on macrophages. This triggers TLR-4, which leads to the release of IL-1, IL-6, IL-8, and TNF
Classic case of polyarteritis nodosa
HBV +, renal failure, skin nodules, nerve defects, purpura
How is hereditary angioedema related to the complement system?
Hereditary angioedema= deficiency in C1 esterase inhibitor C1 esterase inhibitor also breaks down bradykinin. Increased levels of bradykinin ==> angioedema Never give ACE inhibitors to these patients because ACE-i prevent the breakdown of bradykinin
Henoch-Schonlein Purpura
-IgA vasculitis of small vessels (also C3 deposition -follows strep or viral URI -sx: palpable purpura on buttocks and legs, arthritis, abd pain (+ melena) -tx: usually benign, self limited; severe: steroids Tissue biopsy is best test
What are the mechanisms of induration as part of a hypersensitivity reaction?
1. Late type I (due to macrophages, neutrophils ==> release of cytokines). Always preceded by early type I signs (wheezing, urticaria) 2. Arthus reaction (type III). Localized reaction occuring 4-10 hours after exposure. 3. Type IV. Occurs days after exposure (T cell-mediated)
What structures are under-developed in thymic aplasia?
1. Paracortex in lymph nodes 2. Peri-arteriolar sheaths in spleen (+ absent thymus)
Explain the role of NKC in antibody-dependent cellular cytotoxicity (ADCC).
1. Pathogen-infected cell is coated with IgG 2. CD16 on the surface of NKC binds the Fc portion of IgG on these infected cells 3. Leads to the degranulation of the NKC into the lytic synapse (not a phagocytic process)
Describe the four steps of the neutrophil blood stream exit.
1. Rolling (neutrophil slows down and the Sialyl-Lewis X ligand binds to selectin on endothelial cells) 2. Crawling (integrin on the neutrophil cell surface binds to ICAM on endothelial cell) 3. Transmigration (neutrophil binds PECAM-1 between endothelial cells) 4. Migration (chemokines like C5a and IL-8 pull the neutrophil to site of inflammation)
If you can't see a thymic shadow on a CXR in a newborn with recurrent infections, what should you suspect?
1. Thymic aplasia (DiGeorge syndrome) 2. Severe combined immunodeficiency (SCID)
Most specific cell surface marker of monocyte-macrophage cell lineage
CD14
What antibodies place a fetus at greatest risk for neonatal lupus?
Anti-SSA/Ro and Anti-SSB/La
Key antibodies involved in drug-induced lupus
Anti-histone ** Brought on by INH, procainamide, and hydralazine
You notice a persistent swollen gland in a patient with Sjogren's syndrome? What should you immediately r/o?
B cell lymphoma
What are examples of lymphocytes?
B cells, T cells, NK cells
Describe the phrase "left shift"
Bacterial infection triggers the release of more immature neutrophils into the bloodstream
Important characteristics of IgE antibodies
Binds mast cells and basophils ==> release of inflammatory mediators (histamine) Cross-links when exposed to allergen Mediates immediate (type I) hypersensitivity Contributes to immunity to parasites by activating eosinophils
Male smoker with gangrenous extremities that may auto-amputate. Also see superficial nodular phlebitis and Raynaud's phenomenon.
Buerger's dz (thromboangiitis obliterans)
Clinical features of DiGeorge Syndrome
Cardiac defects (Tetralogy of Fallot) Thymic aplasia ==> reduced # of T-cells [reduced T-cell count ==> paracortex hypoplasia in the lymph nodes] Hypocalcemia Genetic disorder caused by deletion of a portion of the long arm of chrom22 Structures from the 3rd and 4th pharyngeal pouches fail to form
p-ANCA vasculitis
Churg-Strauss syndrome Microscopic polyangiitis Antibodies directed against myeloperoxidase (MPO) surrounding the nucleus
Three small vessel ANCA diseases
Churg-Strauss syndrome Wegener's granulomatosis Microscopic polyangiitis **All have pulmonary and renal (crescentic RPGN) involvement
What is the relevance of the CD3 complex?
Critical component of the T-cell receptor The receptor itself is composed of two chains: an alpha and a beta chain The receptor is surrounded by the CD3 complex ==> facilitates transmission of "bound signal" within the cell
Clinical relevance of inflammatory bowel diseases to T-cell immune response?
Crohn's disease: characterized by non-caseating granulomas, Th1-mediated Ulcerative colitis: characterized by crypt abscesses and bleeding ulcers, Th2-mediated
How do cyclosporine/tacrolimus differ from sirolimus?
Cyclosporine and tacrolimus blocks synthesis of IL-2 ==> decreased T-cell activation Sirolimus blocks the response of lymphocytes to IL-2 ==> decreased T-cell and B-cell activation
Steroid hormones are lipid-soluble and cross cell membranes to exert effects intracellularly. In questions about the effects of steroid hormones and glucocorticoids, look for an answer that involves ________.
DNA transcription ** may include changes to cell growth and differentiation or synthesis of proteins
Important characteristics of IgM antibodies
Expressed on surface of naive B cells prior to activation Produced in the primary (immediate) response to antigen Monomer on B cell, but secreted with J chain ==> pentamer Pentamer enables avid binding to antigen while humoral response evolves Can fix complement
What is the target of the rheumatoid factor (RF) antibody?
Fc portion of IgG **Can also be positive in Sjogren's, SLE, Hep B, Hep C, endocarditis
Biopsy findings of medium vessel in polyarteritis nodosa
Fibrinoid necrosis
What are hallmarks of a blood smear in a post-splenectomy (or splenic dysfunction) patient?
Howell-Jolly bodies (nuclear remnants) Thrombocytosis (due to failure to sequester platelets) Leukocytosis (due to failure to sequester WBCs) Target cells (increased membrane area to volume area)
The presence of what cytokines favors a Th1 immune response?
IL-12 (produced by macrophages) IFN-gamma (produced by Th1 cells, inhibits productions of Th2 cells, also stimulates macrophages)
The presence of what cytokines favors a Th2 immune response?
IL-4 (produces IgE to fight parasites) Il-5 (activates eosinophils in the setting of helminth infections and promotes IgA production) IL-10 (inhibits Th1 production) IL-2 (secreted by all T-cells)
Which antibody provides infants with passive immunity that starts to wane after 6 months of age?
IgG
Why is IgM considered a great activator of the complement system?
IgM plays a crucial role in the Classic activation pathway because of its shape The C1 complex must bind two close together Fc portions of an antibody to become activated (binding ==> C1i falls off the molecule ==> C1r and C1s become active) IgM is a pentamer, which facilitates the easy binding of the C1 complex (because the Fc regions are all very close together)
The Th1 cell-mediated immune response is particularly important for what type of infections?
Intracellular infections! These infections "hide" within the cell and cannot be acted upon by antibodies, which makes the Th2 immune response obsolete Mycobacterium tuberculosis: hides within macrophages Listeria: facultative intracellular infection (newborns, elderly have weak Th1 responses and are thus most susceptible) Granulomatous diseases (Th1 cells secrete IFN-y ==> macrophage production ==> giant cells)
Young Asian child with strawberry tongue and diffuse red rash (eventually desquamates on palms and soles)?
Kawasaki's dz (autoimmune attack of medium vessels) Complication: coronary aneurysm ==> MI Treatment: IVIG and ASA Diff dx: scarlet fever from strep pyogenes in the throat (pt's with scarlet fever will have a sore throat)
Immune deficiency in the setting of an attached umbilical cord (> 30 days after birth)?
Leukocyte Adhesion Deficiency Defect in integrins in neutrophils ==> cannot roll, migrate to site of infection
Active immunity
Long-lasting immune protection resulting from exposure to foreign antigens Ex: natural infection, vaccines, toxoid
Important characteristics of IgG antibodies
Main ab in secondary response to an antigen Most abundant ab in serum Fixes complement, opsonizes bacteria, neutralizes bacterial toxins and viruses Only ab that can cross the placenta
Characteristics of live, attenuated vaccines
Microorganism loses pathogenicity but retains capacity for growth in host Induces cellular and humoral responses Pros: induces strong, lifelong immunity Cons: may revert to virulent forms, contraindicated in pregnancy and immunodeficiency
Methotrexate and mycophenolic acid have similar MOA. Which one is considered a better agent?
Mycophenolate inhibits DNA synthesis in lymphocytes ONLY (specific to IMP dehydrogenase in B/T cells). In contrast, methotrexate impacts DNA synthesis in all rapidly-divinding cells ==> pancytopenia, mucositis
Do killed vaccines generate a robust CD8 T-cell response?
NO Killed vaccines are not incorporated into host cells ==> not recognized by MHC I and presented to CD8 T cells. In contrast, live (attenuated) vaccines do create a CD8 T-cell response because virally-infected cells present antigens in the context of MHC Class I
Churg-Strauss Syndrome
Necrotizing granulomatous inflammation with eosinophils involving multiple organs, especially lungs and heart
What are the criteria for diagnosis of SLE?
Need 4/11
Characteristics of killed, inactivated vaccines
Pathogen inactivated by heat or chemicals, but maintains epitope structure on surface Induces humoral response Pros: safer than live Cons: weaker immune response, boosters required
What vasculitis is classically associated with fibrinoid necrosis and transmural inflammation of medium-sized vessels?
Polyarteritis nodosa **Think HBV, neuropathy, renal failure, nodules, purpura
On a basic level, how is polyarteritis nodosa different from other vasculitities?
Polyarteritis nodosa is immune-complex mediated (type III hypersensitivity reaction) Immune complexes can deposit in a multitude of organ systems (nerves, skin, renal system...)
Clinical implications of mutations involving the Fas receptor or Fas ligand
Prevents apoptosis of auto-reactive lymphocytes ==> increased risk of autoimmune disorders like SLE
Important characteristics of IgA antibodies
Prevents attachment of bacteria and viruses to mucous membranes Produced in the GI tract (in Peyer patches) and crosses epithelial cells by transcytosis ==> protects against gut infections Released into secretions (tears, saliva, mucous, breastmilk) Does NOT fix complement
Passive immunity
Rapid, short-term immunity that results from receiving PRE-FORMED antibodies Ex: IgA in breastmilk, maternal IgG crossing placenta, antitoxin, humanized monoclonal antibody
Renal findings in polyarteritis nodosa
Renal failure Immune complex deposition in medium vessels ==> renal ischemia ==> rising BUN and creatinine (Will not see RBC casts and glomerulonephritis)
Classic sign of polyarteritis nodosa on angiogram
Rosay sign= aneurysms in the mesenteric, kidney, and hepatic arteries
You see "lymphocytic sialadenitis" on the path report for a patient. What should you think?
Sjogren's syndrome
40- 65% of patients with primary biliary cirrhosis have what autoimmune disease?
Sjogren's syndrome (can also be associated with scleroderma but to a lesser extent)
In the fetus, before the bone marrow matures, blood cell formation (hematopoiesis) occurs in which organs?
Spleen and liver
Why are patients with splenic dysfunction prone to infection with encapsulated bacteria?
Splenic dysfunction ==> loss of marginal zone macrophage activity Splenic dysfunction ==> loss of splenic B cells ==> decreased activation of complement system ==> loss of opsonization ==> loss of phagocytic activity by macrophages Most common: strep pneumo
What is the relevance of superantigens?
Superantigens are capable of eliciting an extreme T-cell response and can bypass the normal signal transduction pathway (meaning they can bind straight to the TCR) Extreme T-cell response: secretion of massive amounts of IFN-y and IL-2 ==> vasodilation and septic shock Ex: Staph aureus, Strep pyogenes (Group A)
What is the major driver of chronic allograft rejection?
T-cells (lymphocytes) which attack donor organs as they would foreign cells
What is the effect of tuberculosis on innate immunity?
TB blocks the fusion of the phagosome with the lysosome ==> proliferation inside macrophages and protection from adaptive immunity
Young, Asian woman with weak pulses in one arm. BP difference between extremities. Bruits over the arteries. High ESR. What should you clue in on?
Takayasu's arteritis (granulomatous thickening of aortic branch and its arches)
Elderly female with headache and pain on chewing. High ESR. What should you clue in on?
Temporal arteritis (granulomas in the temporal artery system) Start high-dose steroids immediately and get a biopsy Complication: occlusion of the ophthalmic artery ==> blindness
How can you distinguish between SLE and drug-induced lupus?
The presence anti-histone AB indicates drug-induced lupus
Serum levels of ______ and _________ are expected in patients undergoing anaphylaxis.
Tryptase (enzyme specific to mast cells) Histamine
Difference between tuberculoid and lepromatous leprosy?
Tuberculoid: strong cell-mediated Th1 response that serves to limit the infection ==> small skin lesions Lepromatous: diffuse infection due to depressed Th1 response and increased Th2 response (Th2-driven humoral immunity is not capable of controlling the infection because antibodies cannot touch the intracellular bacterial infection)
Patient has palpable purpura. What disease category should you immediately think of?
Vasculitis
Interferon alpha and beta are produced by human cells in response to _________. What are their roles?
Viral infections Suppress viral replication by halting protein synthesis and promoting apoptosis of infected cells
c-ANCA vasculitis
Wegener's granulomatosis Antibodies directed against proteinase 3 (PR3) in the cytoplasm
Immune disorder in the setting of thrombocytopenia?
Wiskott-Aldrich Mutation in WAS ==> compromises cytoskeleton integrity of T-cell ==> improper APC binding and recognition Thrombocytopenia + Eczema + Recurrent Infections [most commonly in males]
Wegener's granulomatosis
vasculitis of the lung and kidney c-ANCA