Flashcards in Immunology Deck (326):
Positive selection location
Negative selection location
MHC class II deficiency
/defect in development of CD4+ cells in the thymus. /no MHC class II so helper cells cannot be selected by positive selection mechanisms in the thymus but CD8 cytotoxic cells can be produced. /also known as type II bare lymphocyte syndrome.
Positive selection mechanism
T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells survive.
Negative selection mechanism
T cells expressing TCRs with high affinity for self antigens undergo apoptosis. Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE).
Autoimmune polyendocrine syndrome-1
deficiency of negative selection.
Lymph drainage of head and neck
Mediastinal lymp nodes drain
trachea and esophagus
Axillary lymph node drainage
Upper limb, breast, skin above umbilicus
Celiac lymph node drainage
Liver + stomach + spleen + pancreas + upper duodenum
Superior mesenteric lymph node drainage
lower duodenum + jejunum + ileum + colon to splenic flexure
Inferior mesenteric lymph node drainage
Colon from splenic flexure to upper rectum
Internal iliac drains
Lower rectum to anal canal (above pectinate line) + bladder + vagina (middle third) + cervix + prostate
testes + ovaries + kidneys + uterus
Superficial inguinal node drains..
anal canal (below pectinate) + skin below umbilicus (except popliteal area) + scrotum + vulva.
dorsolateral foot + posterior calf
thoracic duct drains into..
junction of left subclavian + internal jugular veins
Function of medullary sinus of lymph node
Outside near capsule. Houses reticular cells and macrophages, which perform nonspecific filtration.
Location of B-cells in lymph node
lymph node follicle
Site of b-cell localization and proliferation
Difference between primary follicles and secondary follicles.
Primary follicles are dense and dormant, secondary follicles are activated and have pale central germinal centers.
Function of medulla of lymph node and composition
Consists of medullary cords and medullary sinuses.
Closely packed lymphocytes and plasma cells.
Communicate with efferent lymphatics and contain reticular cells and macrophages.
Where are T cells located in lymph node?
region between follicles and medulla. Contains high endothelial venules through which T and B cells enter from blood.
Sinusoids of spleen
Long, vascular channels in red pulp with fenestrated "barrel hoop" basement membrane.
Where are T cells found in the spleen?
periarteriolar lymphatic sheath (PALS) within the white pulp.
Where are B cells found in the spleen?
Follicles within the white pulp.
Marginal zone of spleen.
Zone between the red pulp and white pulp that contains macrophages and specialized B cells.
Marginal zone of spleen function
Where APCs capture blood-borne antigens for recognition by lymphocytes.
GBS encapsulated or nonecapsulated?
Mechanism for increased susceptibility to encapsulated organisms with splenic dysfunction
Decreased IgM --> decreased complement activation --> decreased C3b opsonization.
Postsplenectomy hematologic findings
1) Howell-Jolly bodies (nuclear remnants)
2) Target cells
3) Thrombocytosis (loss of sequestration and removal)
4) lymphocytosis (loss of sequestration).
Spleen follicle organization
Germinal center surrounded by mantle zone surrounded by marginal zone.
Cortex is dense with immature T cells; medulla is pale with mature T cells and Hassall corpuscles
Contain epithelial reticular cells
T cell and B cell origin
T cells = Thymus (mature in thymus, originate in bone marrow), B cells = Bone marrow.
Thymic hypertrophy seen in...
Innate immunity components
Neutrophils, macrophages, monocytes, dendritic cells, NK cells (lymphoid origin), complement.
Mechanism of innate immunity
What physical barriers does innate immunity have?
epithelial tight junctions + mucus
Proteins secreted by innate immunity
lysozyme, complement, CRP, defensins.
Key features of pathogen recognition in innate immunity
Toll-like receptors (TLRs).
Pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) (eg LPs, flagellin, nucleic acids (viruses))
Components of adapative immunity
T cells, B cells, circulating antibodies
MHC 1 loci
HLA-A, HLA-B, HLA-C (all have 1 letter)
MHC 1 expression
Expressed on all nucleated cells. Not expressed on RBCs.
MHC I vs. MHC II function
MHC 1 present endogenously synthesized antigens (eg viral or cytosolic proteins) to CD8+ T cells. MHC II prsent exogenously synthesized antigens (eg bacterial proteins to CD4+ helper T cells).
protein associated with MHC 1
Antigen loading in MHC 1
Antigen peptides loaded onto MHC I in RER after delivery via TAP (transporter associated with antigen processing).
MHC II loci
HLA-DP, HLA-DQ, HLA-DR (all have 2 letters)
MHC II expression
Expressed on APCs
protein associated with MHC II
Mechanism of MHC II
Antigen loaded following release of invariant chain in an acidified endosome.
Addison disease HLA association
MG HLA association
MS HLA association
RA HLA association
Addison's HLA association
DR3 + DR4
Hashimoto's HLA association
DM1 HLA association
DR3 + DR4
MS HLA association
Goodpasture's HLA association
SLE HLA association
DR2 + DR3
Pernicious anemia HLA association
Hay fever HLA association
Graves HLA association
NK cell mechanism
Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells
What enhances NK cell activity?
IL-2 + IL-12 + IFN-alpha + IFN-beta
What induces NK cells?
Exposure to a nonspecific activation signal on target cell and/or to an absence of class I MHC on target cell surface.
NK cell other mechanism
antibody-dependent cell mediated cytotoxicity
antibody-dependent cell mediated cytotoxicity mechanism
CD16 binds Fc region of bound Ig, activating NK cell
Process of B cell antigen specificity
CD4+ vs. CD8+ cells
CD4 help b cells make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes. CD8 directly kill virus-infected cells.
Where are mature and immature T cells found?
immature in cortex, mature in medulla.
What activates Th1 cells?
What activates Th2 cells?
What activates Th17 cells?
TGF-beta + IL-6
What are cytotoxic T cells activated by?
What induces differentiation of Th1 cells?
IFN-gamma and IL-12
What inhibits TH1 cells?
IL-4 + IL-10 (from Th2 cell)
What do Th2 cells secrete?
IL-4, IL-5, IL-10, IL-13
Th2 cell function
Recruit eosinophils for parasite defense and promote IgE production by B cells
What induces differentiation of Th2 cells?
What inhibits Th2 cells?
IFN-gamma from Th1 cells
macrophage-lymphocyte interaction mechanism
Macrophages and other APCs release IL-12, which stimulates T cells to differentiate into Th1 cells. Th1 cells release IFN-gamma to stimulate macrophages.
Cytotoxic T cell mechanism
1) kill virus-infected, neopalstic, and donor graft cells by inducing apoptosis.
2) release cytotoxic granules containing preformed proteins (eg perforin, granzyme B)
Regulatory T cell mechanism
Maintain specific immune tolerance by suppressing CD4 and CD8 T-cell effector functions.
Regulatory T cell markers
CD3, CD4, CD25, FOXP3
What do activated regulatory T cells produce?
anti-inflammatory cytokines (IL-10 + TGF-beta)
B cells + macrophages + dendritic cells
Caveat about T and B cell activation
Two signals are required for T-cell activation, B-cell activation, and class switching.
Naive T-cell activation
Dendritic cell samples and processes antigen --> dendritic cell migrates to draining lymph node --> T-cell activation (signal 1): antigen is presented on MHC II and recognized by TCR on Th (CD4+) cell. Endogenous antigen is presented on MHC I to Tc (CD8+) cell --> Proliferation and survival (signal 2): costimulatory signal via interaction of B7 proteins (CD80/86) and CD28 --> Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus-infected cell.
B-cell activation and class switching mechanism
1. Th-cell activation.
2. B-cell receptor-mediated endocytosis; foreign antigen is presented on MHC II and recognized by TCR on Th cell.
3. CD40 receptor on B cell binds CD40 ligand (CD40L) on Th cell.
4. Th cell secretes cytokines that determine Ig class switching of B cell. B cell activates and undergoes class switching, affinity maturation, and antibody production.
region of antibody containing variable/hypervariable regions.
What fixes comploment
Fc region of IgM and IgG
unique antigen-binding pocket; only 1 antigenic specificity expressed per B cell.
carbohydrate side chains
Expressed on Fc region
What determines isotype (IgM, IgD, etc)?
Antibody binding and preventing bacterial adherence.
How is antibody diversity generated?
1) Random recombination of VJ (light-chain) or V(D)J (heavy-chain) genes.
2) random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase (TdT)
3) Random combination of heavy chains with light chains
How is antibody specificity achieved?
1) Somatic hypermutation and affinity maturation (variable region)
2) Isotype switching (constant region)
Affinity maturation mechanism
Process by which Th cell-activated B cells produce antibodies with increased affinity for antigen. With repeated exposures to the same antigen, host produces antibodies of successively greater affinities.
Immunoglobulins expressed on mature, naive B cells prior to activation...
IgM and IgD
What mediates isotype switching?
CD40L and cytokines
Immunoglobulin responsible for neutralizing bacterial toxins and viruses
Main antibody in secondary (delayed) response to an antigen
Which immunoglobulins have J chains?
IgA and IgM
IgA in circulation
Exists as a monomer
How does IgA cross epithelial cells?
Most produced antibody overall, but has lower serum concentrations.
What contains IgA
Tears, saliva, mucus, and breast milk.
What is secretory component?
Portion of IgA that IgA picks up from epithelial cells, and which protects Fc portion from luminal proteases.
What is produced in the immediate response to an antigen?
Monomer on B cell, pentamer with J chain when secreted.
Why does IgM exist as a pentamer?
Pentameric form enables avid binding to antigen while humoral response evolves.
Unclear function. Found on surface of many B cells and in serum.
What immunoglobulin has the lowest concentration in serum?
Antigens lacking a peptide component. Thus, they can't be presented by MHC to T cells and are weakly immunogenic.
Example of thymus-independent antigen
Critical function of CD40L
Class-switching. Expressed on helper T cells
What activates acute-phase reactants?
What produces acute-phase reactants
Opsonin; fixes complement and facilitates phagocytosis
CRP clinical significance.
Sign of ONGOING inflammation.
Function of ferritin
Binds and sequesters iron to inhibit microbial iron scavenging.
Functions of fibrinogen
1) coagulation factor
2) promotes endothelial repair
3) correlates with ESR.
Function of hepcidin
1) decreases iron absorption (by degrading ferroportin)
2) decreased iron release (from macrophages)
anemia of chronic disease mechanism
Increased hepcidin due to chronic inflammation.
Serum amyloid A
acute phase reactant
Internalized by macrophages to sequester iron.
Why is albumin downregulated with inflammation?
Reduction conserves amino acids for positive reactants.
gram negative bacteria
What activates classic complement pathway?
IgG or IgM
What activates alternative complement pathway?
Microbe surface molecules
What activates Lectin complement pathway?
Mannose or other sugars on microbe surface
complement proteins involved in anaphylaxis
C3a, C4a, C5a
2) clears immune complexes
Primary opsonins in bacterial defence
C3b and IgG
What prevents complement activation of self cells?
1) decay-accelerating factor (DAF, aka CD55)
2) C1 esterase inhibitor
C1 esterase inhibitor deficiency mechanism
unregulated activation of kallikrein leads to increased bradykinin
Causes complement-mediated lysis of RBCs and PNH
Other name for IL-1
1) causes fever, acute inflammation
2) activates endothelium to express adhesion molecules
3) induces chemokine secretion to recruit WBCs
2) stimulates production of acute-phase proteins
1) Induces differentiation of T cells into Th1 cells
2) activates NK cells
2) activates endothelium
3) causes WBC recruitment
4) vascular leak
Cytokines secreted by macrophages
cytokines secreted by all T cells
IL-2 and IL-3
Stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells
- Supports growth and differentiation of bone marrow stem cells.
- Functions like GM-CSF
What secretes interferon-gamma
NK cells and Th1 cells in response to Il-12 from macrophages
1) stimulates macrophages to kill pathogens
2) inhibits differentiation of Th2 cells
3) activates NK cells to kill virus-infected cells.
4) Increases MHC expression and antigen presentation by all cells.
cytokines secreted by Th2 cells
Il-4,5, and 10
1) induces differentiation of T cells into Th2 cells
2) promotes growth of B cells
3) enhances class switching to IgE
1) promotes growth and differentiation of B cells
2) enhances class switching to IgA
3) stimulates growth and differentiation of eosinophils
1) attenuates inflammatory response
2) decreases expression of MHC class II and Th1 cytokines
3) inhibits activated macrophages and dendritic cells
What is responsible for attenuating the immune response?
TGF-beta and IL-10
Creation AND neutralization of ROS.
NADPH oxidase mechanism
Utilizes NADPH to generate oxygen anions
Protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation.
enzyme in Pseudomonas that generates ROS to kill competing microbes
Glycoproteins synthesized by virus-infected cells that act locally on uninfected cells, priming them for viral defense by helping to selectively degrade viral nucleic acid and protein.
Proteins found on T cells
Associated with TCR for signal transduction.
Binds B7 on APC.
Regulatory T cell markers
B cell markers
3) MHC II
Protein expressed on B cells that binds antigen.
Proteins expressed on macrophages
4) mHC II
5) B7 (CD80/86)
6) Fc and C3b receptors
receptor for PAMPs
NK cell markers
2) CD56 (unique marker for NK)
CD16 on NK cells functions
Binds Fc of IgG
T and B cells need 2 signals to become activated. This is a safety mechanism of self-tolerance.
Cross-link Beta region of T-cell receptor to MHC class II on APCs. Can activate any CD4+ T cell --> massive cytokine release.
Directly stimulate macrophages by binding to endotoxin receptor TLR4/CD14. No Th cells involved.
bacterial examples of antigenic variation
2) borrelia recurrentis
3) N gonorrhoeae
viral examples of antigenic variation
parisitic examples of antigenic variation
half-life of antibodies
When are patients given preformed antibodies (which bugs?)?
"To Be Healed Very Rapidly"
Tetanus, Botulinium, HBV, Varicella, Rabies
When are combined passive and active immunizations needed?
Hep B + rabies exposure
Only live attenuated vaccine given to HIV patients
Live attenuated vaccine mechanism
organism loses its pathogenicity but retains capacity for transient growth within inoculated host.
Live attenuated vaccine pros/cons
Pro: induces strong, often lifelong immunity.
Con: can revert to virulent form.
hep A vaccine: live or killed?
polio (salk) vaccine: live or killed?
BCG: vaccine: live or killed?
varicella vaccine: live or killed?
yellow fever vaccine: live or killed?
measles vaccine: live or killed?
Rabies vaccine: live or killed?
influenza injection vaccine: live or killed?
mumps vaccine: live or killed?
rubella vaccine: live or killed?
polio (sabin) vaccine: live or killed?
site of action of histamine
Type I hypersensitivity mechanism and delayed response.
1) Preformed antibodies on mast cells or basophil (IgE) are cross-linked with free antigens.
2) Delayed response follows due to production of archidonic acid metabolites (eg, leukotrienes).
Type II mechanisms
1) opsonization and phagocytosis
2) Complement- and Fc receptor-mediated inflammation
3) Antibody-mediated cellular dysfunction
Direct Coombs test
Detects antibodies that have adhered to patient's RBCs (eg test Rh+ infant of an Rh- mother)
Indirect coombs test
Detects serum antibodies that can adhered to other RBCs (test an Rh negative woman for Rh positive antibodies)
Acute hemolytic transfusion reaction hypersensitivity type
AIHA hypersensitivity type
Type III hypersensitivity mechanism
Immune complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes.
Polyarteritis nodosa hypersensitivity type
Serum sickness mechanism
Antibodies to foreign proteins are produced. Immune complexes form and are deposited in membranes, where they fix complement, leading to tissue damage. Usually due to drugs acting as haptens.
serum sickness presentation
Fever + urticaria + arthralgia + proteinuria + lymphadenopathy
test for arthus reaction
Arthus reaction mechanism
Local subacute antibody-mediated. Intradermal injection of antigen into presensitized (already has circulating IgG) individual leads to immune complex formation in skin.
Arthus reaction presentation
edema + necrosis + complement activation.
Type IV mechanism
1) Sensitized T cells encounter antigen and release cytokines, leading to macrophage activation.
2) Response does not involve antibodies.
Type IV caveat
Not transferable by serum since cell mediated.
Transplant rejections hypersensitivity type
Febrile nonhemolytic transfusion reaction mechanism
Type II hypersensitivity reaction. Host antibodies against donor HLA antigens and WBCs
Febrile nonhemolytic transfusion reaction presentation
Fever + headaches + chills + flushing
Acute hemolytic transfusion reaction mechanism
Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs).
Acute hemolytic transfusion reaction presentation
Fever + hypotension + tachypnea + tachycardia + flank pain + hemoglobinuria + jaundice (extravascular)
breakdown of RBCs in blood vessels
extravascular hemolysis example
host antibody reaction against foreign antigen on donor RBCs
drug-induced lupus antibody
autoantibodies in polymyositis, dermatomyositis
Anti-Jo-1 + anti-SRP + anti-Mi-2
primary membranous nephropathy autoantibody
antiphospholipase A2 receptor
Anti-Scl-70 (anti-DNA topoisomerase I)
Autoimmune hepatitis type I autoantibody
celiac disease autoantibodies
IgA anti-endomysial + IgA anti-tissue transglutaminase
p-ANCA also known as
c-ANCA also known as
Other impt findings in bruton's
Absenct/scanty lymph nodes and tonsils
Bruton's gene mutation
BTK (tyrosine kinase)
Recurrent bacterial and enteroviral infections after 6 months (after maternal IgG declines).
Most common primary immunodeficiency
Selective IgA deficiency
defect in B-cell differentiation
term for cardiac defects in DiGeorge
How do you test for 22q11 deletion?
Immunodeficiency that prevents after adiminstration of BCG vaccine...
IL-12 receptor deficiency
IL-12 receptor deficiency etiology
decreased Th1 response
Labs in IL-12 receptor deficiency
hyper-IgE syndrome etiology
Deficiency of Th17 cells due to STAT3 mutation, leading to impaired recruitment of neutrophils to sites of infection.
labs in hyper-IgE
Increased IgE + decreased IFN-gamma
Coarse facies, cold (noninflammed) staphylococcal abscesses, retained primary teeth, eczema.
1) Defective IL-2R gamma chain (x-linked)
2) adenosine deaminase deficiency (AR)
Findings in SCIDS
1) Decreased T-cell receptor excision circles (TRECs)
2) absence of thymic shadow on CXR
3) absence of germinal centers
4) absence T cells on flow cytometry.
Findings in ataxia-telangiectasia
1) increased AFP
2) decreased IgA, IgG, and IgE
4) cerebellar atrophy
pathogens in Hyper-IgM
pneumocystis + cryptosporidium + CMV
gene mutation in Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome etiology
T cells unable to reorganize actin cytoskeleton.
lab findings in Wiskott-ALdrich
- decreased to normal IgG, IgM
- Increased IgE, IgA
- fewer and smaller platelets
Increasedd risk of autoimmune disease and malignancy.
Chediak-Higashi defect and etiology
- Defect in lysosomal trafficking regulator gene (LYST).
- Microtubule dysfunction in phagosome-lysosome fusion.
Chediak higashi presentation
1) Recurrent pyogenic infections by staphylococci and streptococci.
2) Partial albinism
3) peripheral neuropathy
4) progressive neurodegeneration
5) infiltrative lymphohistiocytosis.
Findings in Chediak Higashi
1) Giant granules in granulocytes and platelets
3) mild coagulation defects
another name for flow cytometry
Catalase positive organisms
Increased risk for... with deficiency in early complement
T cell deficiency leads to increased risk of...
bacterial infections with decreased granulocytes (neutropenia)
viral infections in B cell deficiency
Poliovirus (live vaccine contraindicated)
Fungal infections in granulocyte deficiency (neutropenia)
cells containing granules. Basophils, eosinophils, neutrophils.
Syngeneic graft (isograft)
Graft from identical twin or clone
Hyperacute graft rejection onset
Hyperacute graft rejection pathogenesis
Pre-existing recipient antibodies react to donor antigen, activating complement.
Hyperacute graft rejection features
Widespread thrombosis of graft vessels --> ischemia/necrosis.
Acute graft rejection timeframe
Weeks to months
Acute graft rejection pathogenesis
Cellular: CD8+ T cells activated against donor MHcs (type IV
Humoral: similar to hyperacute, except antibodies develop after transplant.
Acute graft rejection features
Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate
Chronic graft rejection timeframe
Months to years
Chronic graft rejection pathogenesis
CD4+ T cells respond to recipient APCs presenting donor peptides, including allogeneic MHC.
Both cellular and humoral components (type II and IV)
Chronic graft rejection features
Recipient T cells react and secrete cytokines --> proliferation of vascular smooth muscle + parenchymal atrophy + interstitial fibrosis + ateriosclerosis.
Lung chronic rejection disease
heart chronic rejection disease
kidney chronic rejection
chronic graft nephropathy
liver chronic rejection disease
vanishing bile duct syndrome
Grafted immunocompetent T cells proliferate in immnocompromised host and reject host cells, leading to severe organ dysfunction.
When does GVHD usually occur?
Bone marrow and liver transplants (rich in lymphocytes)
When can GVHD be beneficial?
Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor effect).
1) transplant rejection prophylaxis
Calcineurin inhibitors; binds CYCLOphilin.
Blocks T-cell activation by preventing IL-2 transcription.
nephrotoxic + HTN + hyperlipidemia + neurotoxicity + gingival hyperplasia + hirsitusm
- Calcineuron inhibitor; binds FK506 binding protein FKBP.
- Blocks T-cell activation by preventing IL-2 transcription.
Increased risk of diabetes + neurotoxicity + highly nephrotoxic.
mTOR inhibitor; binds FKBP. Blocks T-cell activation and B-cell differentiation by preventing response to IL-2.
Pancytopenia + insulin resistance + hyperlipidemia.
daclizumab, basiliximab SE's
Edema + HTN + tremor
antimetabolite precursor of 6-mercaptopurine.
- Inhibits lymphocyte proliferation by blocking nucletoide synthesis.
1) Transplant rejection prophylaxis
5) other autoimmune conditions
leukopenia + anemia + thrombocytopenia
Other use for mycophenolate mofetil
mycophenolate mofetil association
Invasive CMV infection
mycophenolate mofetil SE's
GI upset + pancytopenia + HTN + hyperglycemia. Less nephrotoxic and neurotoxic.
corticosteroid immunosuppression mechanism
1) Inhibit NF-kB.
2) Suppress both B- and T-cell function by decreasing transcription of many cytokines.
3) Induce apoptosis of T lymphocytes.
NFAT-P--> NFAT, which is a TF
aldesleukin clinical uses
RCC + metastatic melanoma
Chronic hep B and C, Kaposi sarcoma, malignant melanoma
Thrombopoietin receptor agonists
alemtuzumab clinical use
CLL + MS
bevacizumab clinical uses
CRC + RCC + mac degen
Stage IV CRC + head and neck cancer
B-cell non-Hodgkin lymphoma + CLL + RA + ITP
decoy TNF-alpha receptor. NOT a monoclonal antibody.
Eculizumab clinical use
Paroxysmal nocturnal hemoglobinuria
inhibits osteoclast maturation
RSV F protein