Immunology Flashcards
Hilar Lymph node
lungs
Cervical lymph node
Head and neck
Mediastinal lymph node
trachea and esophagus
Axillary lymph node
upper limb, breast, skin above umbilicus
Celiac lymph node
liver, stomach, spleen, pancreas, upper duodenum
Superior Mesenteric lymph node
lower duodenum, jejunum, ileum, colon to splenic flexure
inferior mesenteric lymph node
colon from splenic flexure to upper rectum
Internal iliac lymph node
lower rectum to anal canal (above pectinate line), bladder, vaginal (middle third), prostate
Para-aortic lymph node
testes, ovaries, kidneys, uterus
Superficial Inguinal
Anal canal (below pectinate line), skin below umbilicus (except popliteal area)
Popliteal lymph node
Dorsolateral foot, posterior calf
Right lymphatic duct
drains right side of body above diaphragm
Thoarcic lymphatic duct
drains everything else into junction of left subclavian and internal jugular veins
What structures are in the lymph node cortex?
Follicles- contain B cells
- Primary follicles: more dense and dormant
- Secondary follicles: lighter and active
What structures are in the lymph node medulla?
Medullary cords- tightly packed lymphocytes and plasma cells
Medullary sinuses- contain reticular cells and macrophages–> communicate with efferent lymphatics
What is the paracortex of the lymph node?
Region between the follicles and the medulla; contains T cells and high endothelial venules through which T-cells and B-cells enter from blood
** Paracortex enlarges in an extreme cellular immune response (viral infection)**
What are the sinusoids of the spleen? Where are they found?
long, vascular channels in the red pulp with fenestrated barrel-hoop basement membranes. Cells mechanically are filtered and damaged cells get devoured by surrounding macrophages
What is in the splenic red pulp?
RBCs and sinusoids
Explain the structure of the white pulp.
White pulp- really is blue = contain lymphocytes
- Contains central arteriole surrounded by periarteriolar lymphatic sheath (T cells)
- Mostly comprised of lymphatic nodules (B cells) –> can mature to germinal center @ marginal zone once antigen presented
What is the marginal zone of the spleen?
The marginal zone is the area between the red pulp and the white pulp; it contains APCs and B cells
Where do T cells mature?
Thymus
Describe the structure of the thymus.
Encapsulated and lobulated
- Cortex is dense with immature T cells = site of positive selection
- Medulla is pale with mature T cells= site of negative selection
What are Hassall corpuscles?
located in the thymus; whorl-shaped clusters of epithelial reticular cells; eosinophilic staining
- reticular epithelial cells function to form a structural network for the thymus
Positive selection
Process in the maturation of T cells. T cells that express a TCR that binds self MHC (I or II) survives. Occurs in the thymus cortex.
Negative selection
Process in T cell maturation. T cells that TCR binds self MHC too tightly undergo apoptosis. Occurs in the thymus medulla.
What cell surface markers to immature T cells express?
TCR that binds self MHC, double positive= CD4+ & CD8+
CD8+
Cytotoxic T cells; kills virus infected, neoplastic, and donor graft cells
-CD8 binds MHC I on virus infected cells
CD4+
Helper T cells; Differentiate into Th1, Th2, Th17 & Treg cells
-CD4 binds MHC II on APCs
Th1 cells
:Helper T cell CD4+, activates macrophages and CTLs
- Macrophages release of IL-12 stimulates Cd4+ T cells to differentiate into Th1 cells
- CELL MEDIATED IMMUNITY
- secretes IFN-gamma to stimulate macrophages, and IL-2 which has autocrine effect of TH1 cell proliferation
- inhibited by IL-4 and IL-10 from Th2 cells
Th2 cells
: helper T cell CD4+; Initiates Ab response, promotes class switching, recruits eosinophils for parasite defense
- HUMORAL IMMUNITY
- Secretes IL-4, IL-5, IL-10, IL-13
- inhibited by IFN-gamma from Th1 cells
CTLs
Kills virus infected, neoplastic, and donor graft cells by inducing apoptosis. Releases cytotoxic granules containing performed proteins
- perforin: delivers content of granules to target cell
- granulysin: antimicrobial, induces apoptosis
- granzyme B: a serine protease, activates apoptosis inside cell
Regulatory T cells
Suppress CD4 and CD8 T cell effector functions
- produce anti-inflammatory cytokines; IL-10 and TGF-B
- identified by expression cell surface markers: CD3, CD4, CD25 and transcription factor FOXP3
Toll-like receptors
cell surface receptors on macrophages, dendritic cells, NK cells that recognize pathogen associated molecular patterns (PAMPs)
MHC I
- encoded by: HLA-A, HLA-B, HLA-C
- expressed on all nucleated cells; none on RBCs
- presents endogenously synthesized antigens to CD8 cells
- antigens loaded onto MHC in RER after delivery via TAP peptide transporter
- B2- microglobulin transports to cell surface
MHC II
- encoded by HLA-DR, HLA-DP, HLA-DQ
- expressed on APCs only
- presents exogenously synthesized antigen
- antigen loaded following release on invariant chain in an acidified endosome
Natural Killer cells
:use perforin and granzymes to induce apoptosis of virally infected cells
- only lymphocyte member of the innate immunity
- induced to kill when exposed to activation signal on target cell or absence of MHC class I
- kills via Ab-dependent cell mediated cytotoxicity (CD16 binds to Fc portion of bound Ig = activates NK cell
What is the significance of costimulatory signaling?
Naive T cell activation
- APCs( Dendritic cells, macrophages, B cells) present antigen via MHCII or host cells present antigen via MHC I to CD4 helper T cells or CTLs respectively [signal 1]
- Costimulatory signal: B7 on APC binds to CD28 on T cell
How do T cells activate B cells?
- CD4 helper cells are activated via APCs
- B cells present antigen via MHC II to TCR on CD4 cell [signal 1]
- B cell is activated when CD40 ligand on T cell interacts with CD40 on B cell surface [signal 2]
- Cytokines secreted by T cell promotes class switching, affinity maturation and antibody production
Antibody structure
2 heavy chains + 2 light chains, 2 Ab binding sites per molecule
-Ab binding site made up of variable region of each chain
Fc portion of Ab
: consists of Constant region of heavy chain, Carboxy terminal, Carbohydrate side chains, Complement binding
-determines isotype (IgG, IgM, etc)
Fab portion of Ab
: Consists of heavy and light chain
- Determines idiotype: specific antigen binding pocket
How is antibody diversity generated?
- Random recombination of VJ (light chain) and VDJ (heavy chain)
- Insertion of DNA nucleotides during recombination by terminal deoxynucleotidyl transferase
- Random combination of heavy and light chains
- Somatic hypermutation following antigen stimulation
IgG
: fixes complement, crosses placenta (passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses
-Most abundant isotype in serum; main antibody in secondary (delayed) response to antigen
IgA
: prevents attachment of bacteria to mucus membranes; released into secretions (saliva, tears, colostrum, mucus)
- monomer in circulation but dimer when secreted
- Most produced antibody overall
- crosses epithelial cells via trancytosis and picks up a secretory component before secretion
IgM
: antigen receptor on the surface of mature B cells
- produced in primary (immediate) response to antigen
- monomer on B cell but pentamer when secreted
IgD
: unclear function, found on surface of mature B cells
IgE
:binds mast cells and basophils; activates eosinophils (worm immunity)
- cross-links when exposed to antigen = immediate type I hypersensitivity
- lowest concentration in serum
Acute Phase Reactants
: produced in acute and chronic inflammation from the liver, induced by IL-6, IL-1, TNF-a, IFN-gamma
- amyloid A, CRP, ferritin, fibrinogen, hepcidin, albumin, transferrin
- amyloid A, CRP, ferritin, fibrinogen, hepcidin concentration increase
- albumin, transferrin concentration decrease
IL-1
aka “osteoclast activating factor”
:causes fever, acute inflammation, activates endothelium to express adhesion molecules, induces chemokine secretion to recruit leukocytes
Hot T-Bone stEAK
IL-1: 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 reactants
IL-6
:causes fever, secreted by Th2 cells, stimulates production of acute phase reactants
IL-8
major chemotactic factor for neutrophils
IL-12
:induces differentiation of T cells into Th1 cells, activates NK cells, secreted by B cells
TNF-a
:mediates septic shock, activates endothelium, causes leukocyte recruitment and vascular leak
IL-2
stimulates growth of helper, cytotoxic and regulatory T cells
IL-3
supports growth and differentiation of bone marrow stem cells; functions like GM-CSF
IFN-gamma
: antiviral and antitumor properties, activates NK cells to kill virus infected cells, increases MHC expression and antigen presentation of in cells
IL-4
:induces differentiation into Th2 cells, promotes growth of B cells, enhances class switching to IgE and IgG
IL-5
:promotes B cell maturation to plasma cells, enhances class switching to IgA, stimulates growth and activation of eosinophils
IL-10
:inhibits actions of activated T cells; secreted by Treg
-TNF-B has similar actions
IFN-a & IFN-B
:interferes with viruses; part of innate response
- IFNs are secreted by virally infected cells and prime nearby uninfected cells = priming
- when virus infects a primed cell, viral nucleic acids activate RNAase L (degrades viral/host mRNA & protein kinase (inhibition of viral/host protein synthesis)
- essentially causes apoptosis –>interrupting viral amplification
Complement functions (4)
- Opsonization: C3b + IgG are key opsonins –> Macrophages have complement and Fc receptors for phagocytosis
- C3b clears immune complexes
- MAC: C5b +C6-C9; important in killing gram negative bacteria
- Anaphylaxis: C3a, C4a, C5a–> binds mast cells and basophils and mediates non-IgE degranulation (histamine)
- Neutrophil chemotaxis: C5a
Hereditary angioedema
Caused by C1 esterase inhibitor deficiency; ACE inhibitors contraindicated
- basically complement system cannot be turned off until all proteins exhausted
C5-C9 deficiency
Increased susceptibility to recurrent Neisseria bacteremia
- Recall: MAC complex plays and important role in eliminating gram negative bacteria
- Gram negative bacteria cannot be displayed by MHC because LPS lacks peptide component
C3 deficiency
Increased risk of severe, recurrent pyogenic sinus and respiratory tract infections; increased susceptibility to type III hypersensitivity reactions
DAF Deficiency
DAF = Decay accelerating factor;
:causes complement mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria
-Recall: PNH caused by deficiency in enzyme necessary to make GPI anchor; DAF is anchored to cell membrane via GPI
Anergy
: mechanism of tolerance where cells are functionally inactive following an encounter with antigen
- T cells become anergic without costimulatory molecule
- B cells also become anergic but to a lesser degree than T cells
Live Attenuated Vaccines
: organism loses it pathogenicity but retains transient growth; induces CELLULAR immunity
- life-long immunity but unsafe in pregnancy or immunodeficiency
Inactivated/Killed vaccines
: pathogen inactivated but cell surface epitope structure important for immune response; HUMORAL immunity response
- safer than live vaccines but often require booster shots
Helper T cell surface markers
TCR, CD3 (signal transduction), CD28 (binds B7 of APC), CD40 ligand, CD4
CTL cell surface markers
TCR, CD3 (signal transduction), CD28 (binds B7 of APC), CD8
B cell surface markers
Ig (binds antigen), CD19/20/21 (signal transduction + EBV receptor), CD40, MHCII, B7
Macrophage cell surface markers
CD14 (TLR that recognizes LPS of gram neg), CD40, B7, MHC II, Fc & complement receptors
NK cell surface markers
CD16 (binds Fc of IgG), CD56 (unique NK marker)
Type I hypersensitivity
- Immediate hypersensitivity; Th2 cells involved in sensitization and Ige class switching
- Re-exposure causes IgE mediated mast cell and basophil degranulation (histamine)
- Delayed response is the result of phospholipid breakdown and synthesis of arachidonic acid derivatives leukotrienes –> vasoconstriction, bronchoconstriction, increased vascular permeability + recruitment of eosinophils w/degranulation
Type II hypersensitivity
Ab mediated cytotoxicity (IgG or IgM); requires prior sensitization
-Antibodies activate complement system, mediate opsonization and subsequent phagocytosis by macrophages, and cause Ab-dependent cell mediated cytotoxicity (NK cells)
Type III hypersensitivity
Immune complex (IgG) mediated destruction -immune complexes activate complement which attracts neutrophils; neutrophils release lysosomal contents
Serum Sickness
Type III hypersensitivity; antiserum or drugs causes formation of immune complexes (IgG) –> complement, neutrophils
- develops 5 days after exposure; characterized by fever, urticaria, arthralgias, proteinuria, lymphadenopathy
Arthus Reaction
Type III hypersensitivity; local intradermal injection of antigen causes formation of immune complexes
- local reaction; edema, necrosis, and activation of complement
Type IV hypersensitivity
Delayed type- Cell mediated; sensitized T cells encounter antigen and then release lymphokines (leads to macrophage activation—> spill out endosomal contents into ECF = damage)
“4 T’s”: T lymphocytes, TB, Touch (contact dermatitis), Transplant rejections
-Candida extract skin test
Blood transfusion reaction: Patient - urticaria, pruritis, wheezing, fever.
Type I hypersensitivity- reaction to plasma proteins in transfused blood
Treat with antihistamines
Blood transfusion reaction: Patient- dyspnea, bronchospasm, hypotension, respiratory arrest, shock.
Anaphylactic reaction. IgA deficient individuals must receive blood products that lack IgA
Blood transfusion rxn: Patient- fever, headaches, chills, flushing
Febrile non-hemolytic transfusion reaction; Type II hypersensitivity rxn. Host antibodies against donor HLA antigens and leukocytes
Blood transfusion rxn: Patient- fever, hypotension, tachypnea, tachycardia, flank pain, hemogoblinemia/jaundice
acute hemolytic transfusion rxn; type II hypersensitivity.
- Intravascular hemolysis (ABO blood group incompatibility) =hemoglobinemia
- extravascular hemolysis (host Ab reaction against foreign antigen on donor RBCs) = jaundice
Patient-Increased susceptibility to catalase positive organisms. What do they have? What test do your run? Results?
Catalase positive organisms PLACESS: Psuedomonas, Listeria, Aspergillus, Candida, E.coli, S. aureus, Serratia
: Chronic granulomatous disease; defect in NADPH oxidase = decreases ROS and absent respiratory burst in neutrophils; X-linked recessive
-Dihydrorhodamine flow cytometry test- expect abnormal result; neutrophils cannot oxidize DHR d/t absent respiratory burst
-Nitroblue tetrazolium dye- expect negative result; NADPH reduces nitroblue to a blue compound; the greater the blue the greater functionality the neutrophil has
Patient- recurrent infections with staph and strep, partial albinism, peripheral neuropathy, progressive neurodegeneration, neutropenia. What do they have? What findings do you expect?
: Chediak-Higashi syndrome; defect in lysosomal trafficking regulator gene (LYST), autosomal recessive. Microtubule dysfunction results in phagosome-lysosome fusion & dysfunctional cellular trafficking
Findings: giant granules in neutrophils and platelets, pancytopenia, mild coagulation defects
pg 13 in pathoma
Patient- recurrent bacterial skin and mucosal infections with absent pus formation, impaired wound healing, delayed separation of umbilical cord (>30 days). What do they have? What findings to you expect?
:Leukocyte adhesion deficiency type 1. Defect in LFA-1 integrin (CD18 subunit) on phagocytes, autosomal recessive; impaired migration and chemotaxis.
-Findings: increased neutrophils but absence of neutrophils at infection site
Recall: marginal pool of neutrophils adhere to lung epithelium via integrins awaiting infection–> impaired adhesion = more PMNs in blood
Patient- failure to thrive, chronic diarrhea, thrush. Recurrent viral, bacterial, fungal, protozoal infections, opportunistic infections. What do they have? Findings? Treatment?
: Severe combined immunodeficiency (SCID). Several types including defective IL-2R gamma chain (most common, X-linked), Adenosine deaminase deficiency (autosomal recessive)
- Findings:Absent CD3+ T cells, decreased T cell receptor excision circles (TRECs), absence of thymic shadow (CXR), decreased Ig of all classes
- Treatment: bone marrow transplant ( no concern for rejection)
Patient- Cerebellar defects, spider angiomas (telegiectasia), recurrent sinopulmonary infections. What do they have? Findings?
: Ataxia-telengiectasia. Defects in ATM gene–> DNA double strand breaks–> cell cycle arrest.
- Findings: Increases AFP (alpha fetoprotein); decreased IgA, IgG and IgE. lymphopenia, cerebellar atrophy.
- Have increased risk of malignancy= impaired DNA repair
Patient- severe pyogenic infections early in life, opportunistic infection with pneumocystis, cryptosporium, CMV. What do they have? Findings?
\:Hyper-IgM syndrome. Commonly d/t defective CD40L on Th cells = class switching defect;X-linked recessive. -Findings: Increased IgM, decreased IgG, IgA, IgE
Patient- Thrombocytopenic purpura, eczema, recurrent infections. What do they have? Findings?
: Winskott-Aldrich syndrome; triad of symptoms. Mutation in WAS gene (X-linked recessive); T cells unable to reorganize actin cytoskeleton
- Findings: decreased to normal IgG, IgM, increased IgE, IgA, fewer and smaller platelets
- have increased risk of autoimmune disease and malignancy
Patient-recurrent bacterial infections and enteroviral infections, and Giardia after 6 months. What do they have? Findings?
: X-linked (Burton) agammaglobulinemia; maternal IgG decreases after 6 months. Defect in BTK, a tyrosine kinase gene–> naive B cells cannot mature to plasma cells. X-linked recessive.
-Findings: decreased Ig of all classes, absent/scant lymph nodes and tonsils
Selective IgA deficiency
:unknown cause; most common immunodeficiency!
Most ASYMPTOMATIC. May see respiratory and GI infections, autoimmune disease, atopy, anaphylaxis to IgA containing products (blood transfusion).
Findings: IgA < 7mg/dL with normal IgG and IgM levels
- commonly associated with celiac disease
Patient- tetany, recurrent viral/fungal infections, conotruncal cardiac abnormalities, craniofacial abnormalities. What do they have? Findings?
:Thymic aplasia or DiGeorge Syndrome. 22q11 deletion; failure to develop 3 and 4 pharynegeal pouches–> absent thymus (T cell deficiency) and parathyroids (tetany from hypocalcemia), conotruncal abnormalities (tetrology of fallot, truncus arteriosis)
-Findings: Decreased T cells, PTH, Ca2+; absent thymic shadow (CXR), 22q11 deletion on FISH
Patient- disseminated mycobacterial and fungal infections after BCG administration. What do they have? Findings?
:IL-12 receptor deficiency, autosomal recessive. Decreased Th1 response.
Findings: decrease IFN-gamma
