Cytokines Flashcards
IL-1
macrophage acute
Causes fever, acute inflammation. Activates endothelium to express adhesion molecules. Induces chemokine secretion to recruit WBCs. Also called osteoclast-activating factor.
“Hot T-bone stEAK”: IL-1: fever (hot). IL-2: stimulates T cells. IL-3: stimulates bone marrow. IL-4: stimulates IgE production. IL-5: stimulates IgA production. IL-6: stimulates aKute-phase protein production.
IL-6
macrophage acute
Causes fever and stimulates production of acute- phase proteins.
TNF-alpha
macrophage acute
Activates endothelium. Causes WBC recruitment, vascular leak.
Causes cachexia in malignancy.
Maintains granulomas in TB.
IL-1, IL-6, TNF-α can mediate fever and sepsis.
IL-8
macrophage recruit
Major chemotactic factor for neutrophils.
“Clean up on aisle 8.” Neutrophils are recruited by IL-8 to clear infections.
IL-12
macrophage recruit
Induces differentiation of T cells into Th1 cells. Activates NK cells.
Facilitates granuloma formation in TB.
IL-2
secreted by t cells
Stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells.
IL-3
secreted by T cells
Supports growth and differentiation of bone marrow stem cells. Functions like GM-CSF.
IFN-gamma
secreted by Th1 cells
Secreted by NK cells and T cells in response to antigen or IL-12 from macrophages; stimulates macrophages to kill phagocytosed pathogens. Inhibits differentiation of Th2 cells.
Induces IgG isotype switching in B cells.
Also activates NK cells to kill virus-infected cells. Increases MHC expression and antigen presentation by all cells. Activates macrophages to induce granuloma formation.
IL-4
Induces differentiation of T cells into Th (helper) 2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG.
Ain’t too proud 2 BEG 4 help.
IL-5
Promotes growth and differentiation of B cells. Enhances class switching to IgA. Stimulates growth and differentiation of Eosinophils.
I have 5 BAEs.
IL-10
Attenuates inflammatory response. Decreases expression of MHC class II and Th1 cytokines. Inhibits activated macrophages and dendritic cells. Also secreted by regulatory T cells.
TGF-β and IL-10 both attenuate the immune response.
IL-13
Promotes IgE production by B cells. Induces alternative macrophage activation.
T Cell Surface
TCR (binds antigen-MHC complex) CD3 (associated with TCR for signal
transduction)
CD28 (binds B7 on APC)
Helper T surface
CD4, CD40L, CXCR4/CCR5 (co-receptors for HIV)
T reg surface
CD4, CD25
B cell surface
Ig (binds antigen)
CD19, CD20, CD21 (receptor for Epstein-Barr
virus), CD40 MHC II, B7
Must be 21 to drink Beer in a Barr
Macrophages surface
CD14 (receptor for PAMPs, eg, LPS), CD40 CCR5
MHC II, B7 (CD80/86)
Fc and C3b receptors (enhanced phagocytosis)
NK cells surface
CD16 (binds Fc of IgG), CD56 (suggestive marker for NK)
Type III Hypersensitivity
Immune complex—antigen-antibody (mostly IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes.
Can be associated with vasculitis and systemic manifestations.
Anti Double stranded DNA antibodies anti Sm antibody o Clinical manifestations o Treatments Avoid sunlight Glucocorticoids Other immunosuppressive agents o Drug induced SLE Antihistone antibodies- characteristic Hydralazine, procainamide, and isoniazide common causes Treat: remove drug Rheumatoid Arthritis Anti-Sm antibody
In type III reaction, imagine an immune complex as 3 things stuck together: antigen- antibody-complement. Examples: SLE Rheumatoid arthritis Reactive arthritis Polyarteritis nodosa Poststreptococcal glomerulonephritis Fever, urticaria, arthralgia, proteinuria, lymphadenopathy occur 1–2 weeks after antigen exposure. Serum sickness-like reactions are associated with some drugs (may act as haptens, eg, penicillin, monoclonal antibodies) and infections (eg, hepatitis B).
Serum Sickness
the prototypic immune complex disease. Antibodies to foreign proteins are produced and 1–2 weeks later, antibody- antigen complexes form and deposit in tissues complement activationinflammation and tissue damage (serum C3, C4).
Arthus reaction
a local subacute immune complex-mediated hypersensitivity reaction. Intradermal injection of antigen into a presensitized (has circulating IgG) individual leads to immune complex formation in the skin (eg, enhanced local reaction to a booster vaccination). Characterized by edema, fibrinoid necrosis, activation of complement.
Type IV Hypersensitivity
Two mechanisms, each involving T cells:
1. Direct cell cytotoxicity: CD8+ cytotoxic T
cells kill targeted cells.
2. Inflammatory reaction: effector CD4+
T cells recognize antigen and release inflammation-inducing cytokines (shown in illustration).
Response does not involve antibodies (vs types I, II, and III).
Examples:
Contact dermatitis (eg, poison ivy, nickel
allergy)
Graft-versus-host disease
Tests: PPD for TB infection; patch test for contact dermatitis; Candida skin test for T cell immune function.
4T’s: T cells, Transplant rejections, TB skin tests, Touching (contact dermatitis).
Fourth (type) and last (delayed).
X-linked (Bruton) agammaglobulinemia
Defect in BTK, a tyrosine kinase geneno B-cell maturation; X-linked recessive (in Boys)
Recurrent bacterial and enteroviral infections after 6 months (maternal IgG)
Absent B cells in peripheral blood,Ig of all classes. Absent/scanty lymph nodes
and tonsils (1° follicles and germinal centers absent)live vaccines contraindicated
Selective IgA deficiency
Cause unknown Most common 1°
immunodeficiency
Majority Asymptomatic Can see Airway and GI
infections, Autoimmune disease, Atopy, Anaphylaxis to IgA in blood products
decrease IgA with normal IgG, IgM levels
increase susceptibility to giardiasis Can cause false-negative celiac
disease test
CVID
Defect in B-cell differentiation. Cause unknown in most cases
May present in childhood but usually diagnosed after puberty
increaserisk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections
decreaseplasma cells,
decrease immunoglobulins
Autosomal dominant hyper-IgE syndrome (Job syndrome)
Deficiency of Th17 cells due to STAT3 mutationimpaired recruitment of neutrophils to sites of infection
Cold (noninflamed) staphylococcal Abscesses, retained Baby teeth, Coarse facies, Dermatologic problems (eczema), increased IgE, bone Fractures from minor trauma
increase IgE
increase eosinophils
Learn the ABCDEF’s to get a Job!
Wiskot Aldrich
Mutation in WAS gene; leukocytes and platelets unable to reorganize actin cytoskeleton defective antigen presentation; X-linked recessive
WATER: Wiskott-Aldrich: Thrombocytopenia, Eczema, Recurrent (pyogenic) infections
increasedrisk of autoimmune disease and malignancy
low to normal IgG, IgM
high IgE, IgA
Fewer and smaller platelets
Chédiak-Higashi syndrome
Defect in lysosomal trafficking regulator gene (LYST)
Microtubule dysfunction in phagosome-lysosome fusion; autosomal recessive
PLAIN: Progressive neurodegeneration, Lymphohistiocytosis, Albinism (partial), recurrent pyogenic Infections, peripheral Neuropathy
Giant granules ( B , arrows) in granulocytes and platelets Pancytopenia Mild coagulation defects
Chronic granulomatous disease
Defect of NADPH oxidase decreasedreactive oxygen species (eg, superoxide) and decreasedrespiratory burst in neutrophils; X-linked form most common
increasedsusceptibility to catalase ⊕ organisms
Recurrent infections and granulomas
Abnormal dihydrorhodamine (flow cytometry) test (green fluorescence) Nitroblue tetrazolium dye reduction test (obsolete) fails to turn blue
Leukocyte adhesion deficiency
Defect in LFA-1 integrin (CD18) protein on phagocytes; impaired migration and chemotaxis; autosomal recessive
Late separation (>30 days) of umbilical cord, absent pus, dysfunctional neutrophils recurrent skin and mucosal bacterial infections
increased neutrophils in blood Absence of neutrophils at
infection sitesimpaired wound healing
SCID
Several types including defective IL-2R gamma chain (most common, X-linked recessive); adenosine deaminase deficiency (autosomal recessive);
RAG mutationVDJ recombination defect
Failure to thrive, chronic diarrhea, thrush
Recurrent viral, bacterial, fungal, and protozoal infections
decreased T-cell receptor excision circles (TRECs)
Part of newborn screening for SCID
Absence of thymic shadow (CXR), germinal centers (lymph node biopsy), and T cells (flow cytometry)
Hyper IgM
Most commonly due to defective CD40L on Th cells class switching defect; X-linked recessive
Severe pyogenic infections early in life; opportunistic infection with Pneumocystis, Cryptosporidium, CMV
Normal or high IgM
super low IgG, IgA, IgE
Failure to make germinal
centers
Sjogren
Autoimmune disorder characterized by destruction of exocrine glands (especially lacrimal and salivary) by lymphocytic infiltrates A . Predominantly affects females 40–60 years old.
Findings:
Inflammatory joint pain
Keratoconjunctivitis sicca ( tear production
and subsequent corneal damage)
Xerostomia (saliva production)mucosal
atrophy, fissuring of the tongue B Presence of antinuclear antibodies,
rheumatoid factor (can be positive in
the absence of rheumatoid arthritis), antiribonucleoprotein antibodies: SS-A (anti- Ro) and/or SS-B (anti-La)
Bilateral parotid enlargement
Anti-SSA and anti-SSB may also be seen in
SLE.
A common 1° disorder or a 2° syndrome associated with other autoimmune disorders (eg, rheumatoid arthritis, SLE, systemic sclerosis).
Complications: dental caries; mucosa-associated lymphoid tissue (MALT) lymphoma (may present as parotid enlargement); risk of giving birth to baby with neonatal lupus.
Focal lymphocytic sialadenitis on labial salivary gland biopsy can confirm diagnosis.
SLE
Systemic, remitting, and relapsing autoimmune disease. Organ damage primarily due to a type III hypersensitivity reaction and, to a lesser degree, a type II hypersensitivity reaction. Associated with deficiency of early complement proteins (eg, C1q, C4, C2)clearance of immune complexes. Classic presentation: rash, joint pain, and fever in a female of reproductive age.prevalence in Black, Caribbean, Asian, and Hispanic populations.
Antinuclear antibodies (ANA)
Sensitive, nonspecific Anti Double stranded DNA antibodies
specific Specific Seen in 1/3 of patients
o Clinical manifestations
o Treatments
Avoid sunlight Glucocorticoids Other immunosuppressive agents
o Drug induced SLE
Antihistone antibodies- characteristic Hydralazine, procainamide, and isoniazide common causes Treat: remove drug
Rheumatoid Arthritis
Anti-Sm antibody Antiphosphlipid antibody Low complement: C3, C4, CH50
RASH OR PAIN:
Rash (malar A or discoid B )
Arthritis (nonerosive)
Serositis (eg, pleuritis, pericarditis) Hematologic disorders (eg, cytopenias) Oral/nasopharyngeal ulcers (usually painless) Renal disease
Photosensitivity
Antinuclear antibodies
Immunologic disorder (anti-dsDNA, anti-Sm,
antiphospholipid)
Neurologic disorders (eg, seizures, psychosis)
rheumatoid factors
80% positive rheumatoid factor
Antibodies against Fc portion of IgG antibody “seropositive” But not specific, other diseases can also have positive rheumatoid factor (SLE,
Sjogren’s) Antibodies to citrullinated peptides (ACPA)
Specific marker for rheumatoid
Scleroderma
Systemic sclerosis. Triad of autoimmunity, noninflammatory vasculopathy, and collagen deposition with fibrosis. Commonly sclerosis of skin, manifesting as puffy, taut skin A without wrinkles, fingertip pitting B . Can involve other systems, eg, renal (scleroderma renal crisis; treat with ACE inhibitors), pulmonary (interstitial fibrosis, pulmonary HTN), GI (esophageal dysmotility and reflux), cardiovascular. 75% female. 2 major types:
Diffuse scleroderma—widespread skin involvement, rapid progression, early visceral involvement. Associated with anti-Scl-70 antibody (anti-DNA topoisomerase-I antibody) and anti-RNA polymerase III.
Limited scleroderma—limited skin involvement confined to fingers and face. Also with CREST syndrome: Calcinosis cutis C , anti-Centromere antibody, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. More benign clinical course.
Hashimoto Thyroiditis
Also called chronic autoimmune thyroiditis. Most common cause of hypothyroidism in iodine- sufficient regions. Associated with HLA-DR3,risk of primary thyroid lymphoma (typically diffuse large B-cell lymphoma).
Findings: moderately enlarged, nontender thyroid. May be preceded by transient hyperthyroid state (“Hashitoxicosis”) due to follicular rupture and thyroid hormone release.
Serology: ⊕ antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies. Histology: Hürthle cells A , lymphoid aggregates with germinal centers B .
Postpartum thyroiditis—mild, self-limited variant of Hashimoto thyroiditis arising < 1 year after
delivery.
adenomatous polyposis
Neoplastic, via chromosomal instability pathway with mutations in APC and KRAS. Tubular B histology has less malignant potential than villous C (“villous histology is villainous”);
tubulovillous has intermediate malignant potential. Usually asymptomatic; may present with occult bleeding.
Lynch syndrome
Previously called hereditary nonpolyposis colorectal cancer (HNPCC). Autosomal dominant mutation of mismatch repair genes (eg, MLH1, MSH2) with subsequent microsatellite instability. ∼ 80% progress to CRC. Proximal colon is always involved. Associated with endometrial, ovarian, and skin cancers.
Opsonization
Conceptually, USMLE likes to test on C3b (Innate) and IgG’s (adaptive) roles as
opsonins. Opsonization dramatically increases kill efficiency, and thus is important for the general ability of the immune system to function.
Angioedema
Individuals with C1 esterase inhibitor deficiency have an inherently overactive kinin system. The only thing keeping it in check is constant degradation by ACE
Giving these patients an ACEi removes the last check on kinin production and can precipitate life threatening edema of the airway mucosa.
Note: It is not the angioedema itself that is life-threatening, it is the resulting asphyxiation
This classically presents as a patient with no asthma history presenting to the ED with marked swelling and respiratory failure after starting an ACEi. They will ask you something about C1INHµ, or kinin involvement. The Tx is Epinephrine and intubation
Follicle Lymph Node
Site of B-cell localization and proliferation. In outer cortex. 1° follicles are dense and quiescent. 2° follicles have pale central germinal centers and are active.
Medulla Lymph Node
Consists of medullary cords (closely packed lymphocytes and plasma cells) and medullary sinuses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages.
Paracortex
Contains T cells. Region of cortex between follicles and medulla. Contains high endothelial venules through which T and B cells enter from blood. Not well developed in patients with DiGeorge syndrome.
Paracortex enlarges in an extreme cellular immune response (eg, EBV and other viral infections paracortical hyperplasialymphadenopathy).
Spleen marginal zone
ontains macrophages and specialized B cells. Site where antigen-presenting cells (APCs) capture blood-borne antigens for recognition by lymphocytes. Located between red pulp and white pulp.
Periarteriolar lymphatic sheath
Contains T cells. Located within white pulp.
Speen follicle
Contains B cells. Located within white pulp.
thymus
Located in the anterosuperior mediastinum. Site of T-cell differentiation and maturation. Encapsulated. Thymus epithelium is derived from third pharyngeal pouch (endoderm), whereas thymic lymphocytes are of mesodermal origin. Cortex is dense with immature T cells; medulla is pale with mature T cells and Hassall corpuscles containing epithelial reticular cells.
Normal neonatal thymus “sail-shaped” on CXR (asterisks in A ), involutes by age 3 years.
T cells = Thymus
B cells = Bone marrow
Absent thymic shadow or hypoplastic thymus
seen in some immunodeficiencies (eg, SCID, DiGeorge syndrome).
Thymoma—neoplasm of thymus. Associated with myasthenia gravis, superior vena cava syndrome, pure red cell aplasia, Good syndrome.
