Immunology/Allergy Flashcards
PAMPs
“pathogen-associated molecular patterns” - present on many microbes and not present on human cells
Endotoxin (LPS) binds what complex on macrophages?
CD14 - triggers TLR4 and cytokine release: IL-1, IL-6, IL-8 and TNF
Mannose (polysaccharide found in bacteria and yeast) binds which receptor to trigger an immune reaction?
mannose-binding lectin (MBL) from liver - activates the lectin pathway on complement activation
Phagocytosis of macrophage components?
reactive oxygen species (O2-) - produced by *NADPH Oxidase and reactive nitrogen intermediates (ONOO-) = peroxynitrate
how does TB block the process of phagocytosis in macrophages?
TB modifies the phagosome so that it is unable to fuse w/ the lysosome leading to proliferation inside the macrophage and protection from antibodies
Chediak-Higashi Syndrome
immune deficiency syndrome that results in failure of lysosomes to fuse with phagosomes - kids will have recurrent pyogenic bacterial infections - also oculocutaneous albinism and progressive neurological dysfunction
Surface receptors on macrophages
CD14 - LPS on gram (-)
Fc receptor - FC on antibodies
C3b receptor - complement
MHCII - CD4 on T cells
B7 - CD28 on T cells
CD40 - CD40L on T cells
the major cytokines release of macrophages
IL-1 = “endogenous pyrogen” act on the hypothalamus and causes fever
TNF-alpha = “cachectin” inhibits lipoprotein in fat tissue reducing FA and leading to *cachexia; also kills tumors in animals and can cause intravascular coagulation - DIC
Both cytokines increase synthesis of endothelial adhesions (allows neutrophils to enter inflamed tissues)
IL-6, IL-8 and IL-12 cytokines released by macrophages
IL-6 - fever and stimulates acute phase protein production in the liver (CRP)
IL-8 - attracts neutrophils
IL-12 - promotes TH1 development
neutrophils rolling mechanism
Rolling - Selectin ligand neutrophils (Silly-Lewis X) binds to E-selectin or P-selectin
neutrophils crawling mechanism
Crawling (tight binding) - neutrophils express integrins and bind ICAM on endothelial cells
neutrophils transmigration
Transmigration - neutrophils bind PECAM-1 between endothelial cells and migrate to the site w/ help from chemokines C5a and IL-8
small granules in neutrophils
alkaline phsophatase, collagenase, lysozyme, lactoferrin; they fuse w/ phagosomes and kill pathogens and also be released into the extracellular space
large granules in neutrophils
acid phosphatase and myeloperoxidase; these fuse w/ the phagosome ONLY (do not get released in extracellular space)
Major contrast w/ neutrophils and macrophages w/ antigen presentation
neutrophils do NOT present antigen (not an APC) and macrophages do present antigen
natural killer cells
CD16 binds to IgG
CD56 aka NCAM (identifying)
MHC I that presents to CD8 T cells
NK cells destroys human cells w/ reduced MHC I
ADCC
antibody-dependent cellular toxicity (ADCC) - antibodies coat pathogen and pathogen is then destroyed in a non-phagocytic process
ex: NK cells (CD16 on NK and Fc of IgG - NK kills cells) and eosinophils (IgE and Fc of IgE - release of toxic enzymes onto parasite)
Eosinophils
stain red due to major basic protein that has a (+) charge; activated by IgE and stimulated by IL-5 from Th2; increased in helminth infections and also seen in many allergic diseases
mast cells and basophils
appear blue
basophils = blood stream
mast cells = tissues
bind the Fc portion of IgE antibodies - cross-linking and *aggregation leads to degranulation of histamine and tryptase
transplant rejections within minutes to hours
hyperacute rejection: due to preformed antibodies (IgG) against graft antigens (ABO or HLA) - this is prevented by cross-matching
will see “white rejection”
gross motting and cyanosis, arterial fibrinoid necrosis and capillary thrombotic occlusion
transplant rejection within 6 months
acute rejection: exposure to donor antigens induces activation of naive immune cells - this is predominantly *cell-mediated (CD8)
biopsy: cellular - lymphocytes/mononuclear infiltrates
tx: immunosuppression
transplant rejection months to years later
chronic rejection: chronic low-grade immune response refractory to immunosuppression will see mixed cell-mediated and humoral response
Hallmark = fibrosis especially in vessels
kidneys: fibrosis of capillaries and glomeruli
heart: narrowing coronary arteries
lung: bronchiolitis obliterans
the most important cytokine mediator in septic shock
TNF-alpha
stimulates systemic inflammation and recruitment of additional leukocytes
HLA-DP, HLA-DQ and HLA-DR genes encode for with protein?
genes on chr 6
MHC class II which are expressed on APCs (B cells, macrophages and dendritic cells)
HLA-A, HLA-B and HLA-C genes encode for which protein?
genes on chr 6
MHC class I which are expressed on all nucleated cells (if not expressed then will be killed by NK cells)
C1 inhibitor (C1INH) deficiency
C1INH prevents C1 mediated cleavage of C2 and C4 thereby limiting activation of complement and it also blocks kvllikrein-induced conversion of kininigen to bradykinin
pt w/ this deficiency leads to elevated bradykinin (bradykinin-associated angioedema) NOTE: ACEi are contraindicated in these pts because they can lead to angioedma as well (precipitate disease episodes)
Adverse effects of corticosteroids on the immune system
neutrophilia (increase in neutrophils) - due to neutrophil demargination: neutrophil recruitment to fight infection is decreased leading to increased risk in infections
CD40L activity
expressed on helper T cells and important in costimulatory for APC
activates macrophages by binding CD40 and secreting TNF-alpha
stimulates class switching in B cells by binding CD40 and secreting IL-2/4
because CD40L is important for B cell class switching a deficiency will lead to hyperIgM syndrome
Sympathetic ophthalmia
traumatic injury in one eye that results in granulomatous inflammation of BOTH the injured and noninjured eye - occurs due to robust T-cell response to previously sequestered antigens in the eye that display *immune privilege
age-related immune decline
also called immunosenescence - loss of telomere length affects rapidly dividing cells such as immune cells leading to decreased production of naive B and T lymphocytes - these changes impair the adaptive immune response to novel (new) antigens such as pathogens or vaccinations - can predispose pts to vaccine failure and increases susceptibility to infections
skin test
delayed-type hypersensitivityskin test to screen for cellular immunodeficiency. the predominate cell responsible for a positive test would be T cells
mellatoproteinases
zince-containing enzymes that degrade components of the ECM and basement membrane, which is composed of laminin and collagens IV and VII
facilitate basement membrane penetration (invasion of malignancies)
type I hypersensitivity
immediate reaction to antigens (mins) due to preformed IgE antibodies from primary exposure: antibodies bind and cross-link and aggregate to mast cells and cause mast cell degranulation
all because IgE antibodies (IgG is normal response) **IL-4 is the key cytokine for IgE
Type I hypersensitivities reactions
Skin: urticaria (hives)
Resp: rhinitis or wheezing
Eyes: conjunctivitis (itchy red eyes)
GI: diarrhea
Anaphylaxis - can lead to shock and death tx: epinephrine
Type I hypersensitivities examples
asthma
penicillin drug allergy
seasonal allergies
allergic conjunctivitis
peanut allergy
shellfish allergy
type II hypersensitivity
antibodies IgG or IgM directed against OWN tissue antigens - they are binding normal structures, there are 3 mechanisms:
- phagocytosis (Fc receptors or C3b)
- complement-mediated lysis (classical complement)
- antibody-dependent cytotoxicity (ADCC)
Type II hypersensitivities examples
Rheumatic fever - strep antibodies cross-react w cardiac myocytes
Exposure to wrong blood type - RBC lysis by circulating IgG (erythroblastosis fetalis Rh- mothers w/ Rh+ babies)
Autoimmune hemolytic anemia - methyldopa and penicillin: drugs bind to surface of RBCs or w mycoplasma pneumonia: induces RBC antibodies
Type III hypersensitivities
antigen-antibody (IgG) complex forms and deposits in tissues; two types:
- generalized - serum sickness
- localized - Arthus reaction
Serum sickness form of type III hypersensitivity reaction
immune complexes (IC) deposits in lots of places (skin, kidneys, joints) causes systemic disease - trigger complement activation (Fc receptors)
Arthus reaction form of type III hypersensitivity reaction
local tissue reaction (unlike serum sickness - systemic)
injection of antigen will bind w/ preformed antibodies and form immune complexes (IC) locally; 4-10 hours later (not mins like type I)
Type IV delayed type hypersensitivity
classic example: PPD test for TB
also contact dermatitis - poison ivy or chemical/oils/dyes that attach to skin cells
12-48 hours after exposure
What is the likelihood of a sibling with the same mother and same father being a perfect MHC match for transplant donation?
25%
Graft vs. Host Disease
mostly a complication of bone marrow transplant but can also occur in organ rich in lymphocytes - liver; the donated (grafted) *T cells (CD8) react to recipient cells, they see the recipient as foreign (the opposite of rejection - here the tissue is rejecting the body)
symptoms:
Skin: rash
GI: diarrhea, abdominal pain
Liver: increased LFT and bilirubin
X-linked agammaglobulinemia
X-linked defect in BTK gene resulting in failure of B cells to mature (light chains not produced); recurrent bacterial infections and enteroviral infection after 6 months due to loss of maternal antibodies (IgG)
Findings: loss of mature B cells (CD19, CD20 and BCR), underdeveloped germinal centers
Tx: IV Igs
Selective IgA deficiency
defective IgA - most pts are Asymptomatic but symptomatic pts will have Airway and GI infections from Giardiasis; associated w Autoimmune disease (SLE and RA), Atopy, and Anaphylaxis to IgA containing products (blood transfusions)
labs: low IgA but IgM and IgG will be normal
Special features: false positive B-HCG pregnancy test
Common variable immunodeficiency (CVID)
defective in B cell maturation - loss of plasma cells and antibodies; often sporadic - no family hx
Normal B cell count but absence of antibodies (usually IgG but can be IgM to IgA - it is variable)
majority of 20-45 yr old pt (contrast w. X-linked agammaglobulinemia when baby after 6 months - infancy)
DiGeorge Syndrome
22q11 deletion failure of 3/4th pharyngeal pouches to form leading to thymus and parathyroids
Classic triad:
loss of thymus (loss of T cells)
loss of parathyroid glands (hypocalcemia)
congenital heart defects
can also see facial abnormalities - cleft palate
**DO NOT confuse w/ SCID - calcium will be normal
Hyper-IgE Syndrome
aka Job’s syndrome
deficiency in Th17 cells due to a STAT3 mut leading to an impaired recruitment of neutrophils
Labs: overproduction of IgE (eosinophils/histamine) and decreased IFN-gamma
FATED
coarse Facies, cold (noninflamed) staph Abscesses, retained primary Teeth, increased IgE and Derm probs (eczema)
Classic case: newborn baby w/ deformed face or teeth, a diffuse rash (eczema) with a skin abscesses that are “cold” and also recurrent infections without fever, what should you suspect?
Hyper-IgE Syndrome aka Job’s syndrome
deficiency in Th17 cells due to a STAT3 mut leading to an impaired recruitment of neutrophils
Labs: overproduction of IgE (eosinophils/histamine) and decreased IFN-gamma
Chronic mucocutaneous candidiasis
T cell dysfxn defects in AIRE genes; AIRE associates w lectin-1 and this responds to Candida antigens - defect = recurrent candida infections
noninvasive Candida albicans infections of skin and mucous membranes (thrush); associated w endocrine dysfunction
Classic case: child w/ recurrent thrush and diaper rash with endocrine dysfunction should make you suspect what?
Chronic mucocutaneous candidiasis; T cell dysfxn defects in AIRE genes; AIRE associates w lectin-1 and this responds to Candida antigens - defect = recurrent candida infections
Severe Combined Immunodeficiency (SCID)
loss of T cells and B cells; loss of thymus shadow; loss of germinal centers in nodes
due to either X-linked defective IL-2R or AR adenosine deaminase deficiency (ADA) - fins to convert adenosine to inosine
susceptible to many infections screen w: TRECs tx: bone marrow transplant
Ataxia Telangiectasia
AR defective ATM gene in chr 11; repairs dsDNA breaks via non homologous end-joining (NHEJ) defective = failure to repair DNA mut
pts will have hypersensitivity of DNA to ionizing radiation
triad:
Ataxia, spider Angiomas and IgA deficiency
Labs: increased AFP, decreased IgA, IgG and IgE, increased risk of lymphoma and leukemia
Hyper IgM Syndrome
class switching disorder due to failure of B cells (CD40) to T cells (CD40L) binding so B cells make IgM only (70% of cases are T cell prob w/ CD40L)
Labs: increased IgM and other antibodies are absent
Wiskott-Aldrich Syndrome
X linked disorder of WAS gene leading to WASp absence/dysfxn which is necessary for T cell cytoskeleton - T cells cannot properly react to APCs
Immune dysfxn - decreased platelets and eczema, elevated IgE and IgA tx: bone marrow transplant
WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent infections
Leukocyte Adhesion Deficiency
defect in LFA-1 integrin (CD18) protein on phagocytes - impaired migration (roll) and chemotaxis
delayed separation of the umbilical cord (>30 days) and presents w/ a umbilical stump infection
increased neutrophils in blood (neutrophilia) but absence at infection site (no pus/delayed wound healing)
Chediak-Higashi Syndrome
failure of lysosomes to fuse w phagosome due to mut in lysosomal trafficking regulator (LYST) gene; causes microtubule dysfxn
PLAIN: Peripheral neurodegeneration, Lymphohistiocytsis, Albinism,
Recurrent infections, and peripheral Neuropathy (often wheelchair bound)
Chronic Granulomatous Disease (CGD)
loss of NADPH oxidase leads to decreased ROS and respiratory burst in neutrophils needed to kill catalase (+) organisms
catalase (+) organisms:
Staph aureus
Pseudomanas
Serratia
Nocardia
Aspergillus (fungi)
Test: Nitroblue tetrazolium test - absence of NADPH oxidase - cells do not turn blue (more blue = more NADPH present)
NSAIDs
agents that reversibly inhibit COX 1 and COX 2
Acute interstitial nephritis caused by NSAIDs
hypersensitivity reaction triggered by drugs; inflammation of the interstitum “space between cells” (not the nephron itself)
classic finding: urine eosinophils
Classic case: pt takes NSAID then days to weeks later they present w fever and rash, oliguria and increased BUN/Cr and then eosinophils in the urine
Acute interstitial nephritis caused by NSAIDs; hypersensitivity reaction triggered by drugs; inflammation of the interstitum “space between cells” (not the nephron itself)
COX-2 inhibitors
celecoxib
reversibly inhibits COX-2 only so there is less risk of GI ulcers/bleeding
Adverse effects of increased CV events (MI/strokes) and sulfa allergy
Glucocorticoids
steroids that easily diffuse across cell membranes, bind glucocorticoid receptor (GR) the complex translocates into the nucleus and then alters gene expression
MOA of Glucocorticoids
- inactivation of NF-kB: controls synthesis inflammatory mediators
Other effects: neutrophilia (increased WBCs) - more neutrophils in blood and less at infection
Side effects of chronic glucocorticoids use
skin: skin thinning (paper thin) and easy bruising; Cushingoid appearance/weight gain - truncal obesity, buffalo hump and moon facies; Osteoporosis and hyperglycemia - increased liver gluconeogenesis; cataracts, myopathy and gastritis/peptic ulcers and avascular necrosis
Avascular necrosis
osteonecrosis - associated with long tern steroid use - bone collapse of the femoral head
Abrupt discontinuation in long-term steroid use
Adrenal insufficiency due to long term suppression of the HPA axis; symptoms (adrenal crisis):
hypotension/shock, anorexia, n/v, abdominal pain, weakness, fever and confusion or coma
Cyclosporine and Tacrolimus
immunosuppressive drugs that both inhibit calcineurin (which activates NFAT - nuclear factor of activated T cells) - this is important to transcription of many cytokines (IL-2)
Adverse effect: Nephrotoxicity (most important) - vasoconstriction of afferent/efferent arterioles
two unique side effects of cyclosporine
these are not reported w tacrolimus - gingival hyperplasia and hirsutism
Sirolimus
kidney transplant immunosuppressive; inhibits mTOR (does NOT inhibit calcineurin); blocks response to IL-2 in B and T cells: the cell cycle arrest in the G1-S phase so there is no growth/proliferation
Adverse effects of Sirolimus
anemia, thrombocytopenia and leukopenia, hyperlipidemia (inhibition of lipoprotein lipase) and hyperglycemia (insulin resistance)
Coronary Stents
“drug-eluting stents” (DES) coated with anti-proliferating drug that blunts scar tissue growth (restenosis)
Methotrexate
used as a chemotherapy and to tx some autoimmune disease; mimics folic acid - inhibits dihydrofolate reductase
Side effects of Methotrexate
- myelosuppression - reversible w leucovorin “leucovorin rescue”
- stomatitis/mucositis (mouth soreness)
- abnormal LFTs and GI upset
Mycophenolic acid (mycophenolate)
aka CellCept
immunosuppressive drug that inhibits IMP dehydrogenase; the rate limiting step in purine synthesis in lymphocytes ONLY - decreased nucleotides leads to decreased DNA synthesis in T and B cells
Cyclophosphamide
power immunosuppressant agent used in vasculitis and glomerulonephritis; it is a prodrug that requires activation by the liver (P450); it is an “alkylating agent” that causes DNA to cross link to inhibit DNA replication and cause cell death
Unique side effects of hemorrhagic cystitis - acrolein is toxic to the bladder and SIADH - hyponatremia that leads to seizures
Azathioprine
immunosuppressive that is used in transplants and autoimmune disease; prodrug that is converted to 6-Mercaptopurine (6-MP) which competes for binding to HGPRT
Azathioprine
immunosuppressive that is used in transplants and autoimmune disease; prodrug that is converted to 6-Mercaptopurine (6-MP) which competes for binding to HGPRT
Muromonab-CD3
monoclonal antibody that is used in organ transplants binds to CD3 and blocks T cell activation; leads to T-cell depletion from circulation
Unique side effects: cytokine release syndrome - occurs after 1st or 2nd dose - fevers, rigors, n/v, diarrhea and hypotension
Infliximab
antibody against TNF-alpha used in RA and Crohn’s; “chimeric” - both mouse and human components
there is a risk of reactivation of TB - PPD screening is done prior to tx
Etanercept
TNF-alpha inhibitor made by recombinant DNA; it is an “decoy receptor” that binds TNF binds instead of binding the actual TNF-alpha receptor
pt w Common variable immunodeficiency (CVID) have an increased risk of developing which other disorders?
autoimmune disorders and lymphoma
Which GI disease has a high association with IgA deficiency?
Celiac’s disease
Autoimmune diseases are caused by what broad defect in the immune system?
loss of self-tolerance (central - thymus/bone marrow or peripheral - lymph nodes)
NOTE: negative selection is very important for T cells so they do not attack self tissue
Effects of IL-2
produced by CD4, CD8 and NK cells and has strong proinflammatory and some anti-inflammatory effect; high-dose IL-2 therapy can be used for advanced renal cell carcinoma and metastatic melanoma; this can lead to long-lasting remission due to increased cytotoxic activity of NK cells against the tumor
Programmed cell death protein 1 (PD-1)
PD-1 is an immune checkpoint inhibitor that down-regulates the T-cell response; neoplastic cells and chronic viral infections often exploit this receptor via over expression of PD-1 ligand; PD-1 ligand inhibits restore the T-cell response, allowing cytotoxic T-cells to kill infected or neoplastic cells
X-linked agammaglobulinemia
X-linked agammaglobulinemia is characterized by low or absent circulating mature B cells (CD19, CD20, Cd21) and pan-hypogammaglobulinemia; affected pts have increased susceptibility to pyogenic bacteria, enteroviruses, and Giardia lambda due to the absence of opsonizing and neutralizing antibodies
Splenectomy
the spleen acts as both a blood filter capable of removing circulating pathogens and as a major site of opsonizing antibody synthesis; splenic pts are prone to infections caused by encapsulated organisms (Strep pneumonia, H. influenza and Neisseria meningitidis)
