Immunology Flashcards
Lymph node
A secondary lymphoid organ that has many afferents (to the lymph node) and 1 or more efferents (away from lymph node).
Encapsulated, with trabecular.
Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune response activation
Lymph node follicle
Site of B cell localization and proliferation
Located in outer cortex of lymph node
Primary follicles are dense and dormant
Secondary follicles have pale central germinal center and are active
Medulla
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
House T cells
Region of cortex between follicles and medulla
Contains high endothelial venues through which T cells and B cells enter from the blood
Not well developed in patients w/ DiGeroge syndrome
Paracortex enlarges in an extreme cellular immune response such as response to viral infection
Lymph drainage
Cervical: head and neck
Hilar: lungs
Mediastinal: esophagus and trachea
Axillary: upper limb, breast, skin above umbilicus
Celiac: liver, stomach, spleen, pancreas, upper duodenum
Superior mesenteric: lower duodenum, jejunum, ileum, colon to splenic flexure
Inferior mesenteric: colon from splenic flexure to upper rectum
Internal iliac: lower rectum to upper anal canal, bladder, vagina, prostate
Para-aortic: uterus, ovaries, testes, kidneys
Superficial inguinal: lower anal canal, skin below umbilicus
Popliteal: foot, calf
Right lymphatic duct: drains right side of body above diaphragm
Thoracic duct: drains everything else into junction of left subclavian and internal jugular veins
Sinusoids of spleen
Long, vascular channels in red pulp with fenestrated “barrel hoop” basement membrane where macrophages are found nearby
T cells are found in periarterial lymphatic sheet within white pulp
B cells are found in follicles within the white pulp
The marginal zone (in between white and red pulp), contains APCs and specialized B cells and is where APCs present blood-borne antigens
Macrophages in spleen remove encapsulated bacteria (SHiNE SKiS)
Splenic dysfunction leads to decreased opsonization and increased susceptibility to encapsulated organisms
Thymus
Site of T-cell differentiation and maturation (B cell mature in bone marrow)
From epithelium of 3rd pharynges pouches
Cortex is dens with immature T cells, medulla is pale with mature T cells
Hassall corpuscles contain epithelial reticular cells, which help T cells mature by exposing them with wide variety of self genome that they express
Innate immunity
Neutrophils, macrophages, dendritic cells, NK cells, complements
Resistance persists through generations and does not change within an organism’s lifetime
Nonspecific response to antigens
Occurs rapidly (minutes to hours)
Physical barrier include epithelial junctions and mucus
Secret lysozymes, complements, CRPs, and defensins
TLR: pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMP) such as LPS, flagellin, ssRNA (viruses)
Adaptive immunity
T cells, B cells, antibodies
Variation through VDJ recombination during lymphocyte development and microbial resistance not heritable
Highly specific to specific antigens
Develops over long periods of time, but memory response is much faster
Secrete immunoglobulins
Memory cells: activated B and T cells, subsequent exposure to a previously encountered antigen leads to stronger and quicker immune response
MHC I
Coded by HLA genes
HLAA, B, C
Binds to TCR and CD8
Expressed on all nucleated cells. Not expressed on RBCs
Present endogenously synthesized antigens (e.g. viral) to CD+ cytotoxic T cells
Antigen peptides loaded onto MHCI in RER after delivery via TAP transporter w/ help of Beta2 microglobulin
MHC II
Coded by HLA genes
HLADR, DP, DQ
Binds to TCR and CD4
Expressed only in APCs
Present exogenously synthesized proteins (e.g. bacterial, viral capsid) to T-helper cells
Antigen loaded following release of invariant chain in an acidified endosome
Natural killer cells
Use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells
Only lymphocyte member of innate immune system
Activity enhanced by IL2, IL12, IFNalpha, and IFNbeta
Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of class I MHC on target cell surface
Also kills via antibody dependent cell-mediated cytotoxicity (CD16 binds to Fc region of bound Ig activating the NK cell)
B cell functions
Recognize antigen: undergoes somatic hypermutation to optimize antigen specificity
Produce antibody: differentiate into plasma cells to secrete specific immunoglobulin
Maintain immunologic memory: memory B cells persist and accelerate future response to antigen
T cell functions
CD4+ T cells help B cells make antibody and produce cytokines to activate other cells of immune system
CD8+ T cells kill virus-infected cells directly
Delayed cell-mediated hypersensitivity (type 4)
Acute and chronic organ rejection
T cell differentiation
Bone marrow: T cell precursors synthesized
Thymus cortex: positive selection
Thymus medulla: negative selection
Lymph node: Tc cells and Th cells are distributed
Positive selection
Thymic cortex
T cells expressing TCRs capable of binding self MHC molecules survive
Apoptosis in T cells unable to recognize
Negative selection
Thymic medullar
T cells expressing TCRs with high affinity for self-antigens undergoes apoptosis
Remaining cells survive
Naive T cell activation
- Foreign body is phagocytksed by dendritic cell
- Foreign antigen is presented on MHCII and recognized by TCR on Th cell. Antigen presented on MHCI to Tc cells
- Costimulatory signal is then given by interaction of B7 (from dendritic cell) and CD28 (T cells) after MHC/TCR binding
- Th cell activates and produce cytokines
- Tc cells activates and is able to recognize and kill virus infected cells
B cell activation and class switching
- Th cell activation
- B cell receptor-mediated endocytosis, foreign antigen is presented on MHCII and recognized by TCR on Th cell
- Costimulatory signal is given by CD40 ligand (Th cell) interaction w/ CD40 of B cell after MHC/TCR binding
- Th cell secrets cytokines that determines Ig class switching of B cell.
- B cell activates and undergoes class switching, affinity maturation, and antibody production
Th1 cells
Secrete IFNgamma
Activates macrophages and Tc cells
Inhibited by IL4 (secreted from Th2 cells) and IL10 (secreted from Tregs)
Th2 cells
Secrete IL4, IL5, IL6
Recruits eosinophils for parasite defense
Promotes IgE production by B cells
Inhibited by IFNgamma (secreted by Th1)
Macrophage-lymphocyte interaction
Macrophages release IL12, which stimulates T cells to differentiate into Th1 cells
Th1 cells release IFNgamma to stimulate macrophages
Tc cells
Kill virus infected, neoplastic, and donor graft cells by inducing apoptosis
Release cytotoxic granules containing perforin (helps to deliver the content of granules into target cells) and granzyme (serene protease, activates apoptosis inside target cell), andgranulysin (antimicrobial, induce apoptosis)
Regulatory T cells (special Th2 cells)
Help maintain specific immune tolerance by suppressing CD4 and CD8 T cell effector functions
Identified by expression of surface markers CD3, CD4, CD25, and transcription factor FOXP3
Activated Treg cells produce anti-inflammatory cytokines and TGFbeta
Antibody structure and function
Variable region of L and H chains recognize antigens
Fc region of IgM and IgG fixes complements
Heavy chain contributes to Fc and Fab fractions
Light chain contributes to only Fab fraction
Fab: antigen binding fragment, determines idiotype or the unique antigen binding pocket (only 1 antigenic specificity expressed per B cell)
Fc: Constant, Carboxyl terminal, Complement binding, Carbonhydrate side chains Determines isotype (IgM, IgG, etc)
Antibody diversity is determined by:
Random “recombination” of VJD/VD genes
Random combination of heavy chains w/ light chains
Somatic hypermutation (following antigen stimulation)
Addition of nucleotides to DNA during recombination
IgG
Main antibody in 2ndary (delayed) response to antigen.
Most abundant isotope in serum
Fixes complements, cross placenta, opsonizes bacteria, neutralizes bacteria toxins and viruses (prevent entry)
IgA
Prevents attachment of bacteria and viruses to mucus membranes
Does not fix complements
Monomoer (in circulation) or dimer (when secreted)
Crosses epithelial cells by transcytosis
Most produced antibody overall, but majority released into secretions (tears, saliva, mucus)
IgM
Produced in the primary response to antigen (immediate)
Fixes complements but does not cross the placenta
Antigen receptor on the surface of B cells
Monomers on B cell or pentamers when secreted
Pentamer allows it to efficiently trap free antigens out of tissue while humoral response evolves
IgD
Unclear function
Found on surface of many B cells and in serum
IgE
Binds mast cells and basophils
Cross-linked when exposed to allergen, mediating immediate (type 1) hypersensitivity through release of inflammatory mediates such as histamine
Mediates immunity to worms by activating eosinophils
Lowest concentration in serum
Thymus independent antigens
Antigen lacking a peptide component (LPS), cannot be presented by MHC to T cells
Weakly or nonimmunogenic: vaccines from these often require boosters or conjugation w/ peptides
Thymus dependent antigens
Antigens containing a peptide component
Class switching and immunological memory occur as a result of direct contact of B cells w/ Th cells
Acute phase reactants
Factors released in response to inflammation, produced by liver and induced by IL1, IL6, TNFalpha, and IFNgamma
Serum amyloid A: prolonged elevation and lead to amyloidosis
CRP: opsonin, fixes complements and facilities phagocytosis
Ferritin: binds and sequesters iron to inhibit microbial iron scavenging
Fibrinogen: coagulation factor, promotes endothelial repair
Hepcidin: prevents release of iron bound by ferritin (anemia of chronic disease)
Albumin (decreased): reduction conserves amino acid for positive reactants
Transferrin (decreased): internalized by macrophages to sequester iron
Complement functions
System of interacting plasma proteins that play a role in innate immunity and inflammation
Membrane attack complex (MAC) defense against gram-negative bacteria
C3b: opsonization, clear immune complexes
C3a, C4a, C4a: anaphylaxis
C5b-9: cytolysis activated w/ MAC
Complement activation
Classic pathway: antigen-antibody complex –> C1 –> C3 convertase –> C5 convertase –> MAC –> lysis
Alternative pathway: microbe surface molecule–> C3 –> C3b –> C3 convertase –> C5 convertase –> MAC –> lysis
Lectin pathway: mannose or other microbial sugar –> C1-like complex –> C3 convertase –> C5 convertase –> MAC –> lysis
Complement inhibition
Decay-accelerating factor (DAF/CD55), C1 esterase inhibitor
Prevent complement activation on self cells (RBCs)
C1 esterase inhibitor deficiency
Hereditary angioedema (inflammation 2ndary to lack of inhibition of complements)
ACE inhibitors are contraindicated
C3 deficiency
Increase risk of severe, recurrent pyogenic sinus and respiratory tract infections
Increased susceptibility to typeIII hypersensitivity
C5-C9 deficiency
Increase susceptibility to recurrent Neisseria bacterimia
DAF deficiency
Complement mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria
IL1
Secreted by macrophages
Endogenous pyrogen, causes fever and acute inflammation
Induces chemokine secretion to recruit leukocytes
IL2
Secreted by all T cells
Stimulate growth of ALL T cells
IL3
Secreted by all T cells
Suppor the growth and differentiation of bone marrow stem cells into lymphoid and myeloid progenitors
IL4
Secreted from Th2 cells
Induce differentiation into Th2 cells
Promote growth of B cells
Enhances class switching to IgE and IgG
IL5
Secreted by Th2 cells
Promote differentiation of B cells
Enhances class switching to IgA
Stimulate growths and differentiation of eosinophils
IL6
Secreted by macrophages
Causes fever and stimulate production of acute phase proteins
IL8
Secreted by macrophages
Major chemotactic factor for neutrophils, neutrophils are recruited to clear infections
IL12
Secreted by macrophages
Induce differentiation of T cells into Th1 cells
Activates NK cells
TNFalpha
Secreted by macrophages
Mediates septic shock
Activates endothelium causing leukocyte recruitment and vascular leak
IFNgamma
Secreted by Th1 cells
Has antiviral and antitumor properties
Activates NK cells to kill virus-infected cells
Increases MHC expression and antigen presentation in all cells
IFNalpha and IFNbeta
Part of innate host defense against both RNA and DNA viruses
Glycoproteins synthesized by viral-infected cells that act locally on uninfected cells, “priming” them for viral defense
Viral dsRNA in primed cells activates:
RNAase: degradation of viral/host mRNA
Protein kinase: inhibition of viral/host protein synthesis
Essentially results in apoptosis of infected cell and thereby interrupting w/ viral amplification
Anergy
Self-reactive T cells become nonreactive without costimulatory molecule
Passive immunity
Receiving preformed antibodies
Rapid onset
Short life span of antibodies
IgA in breast milk, maternal IgG crossing placenta, humanized monoclonal antibodies injected
Active immunity
Exposure to foreign antigen
Slow onset
Long lasting protection (memory)
Natural infection, vaccination
Hypersensitivity type 1
Anaphylactic and atopic
Free antigen cross-links IgE on presensitized mast cells and basophils, triggering immediate release of vasoactive amines (histamine) that act at post capillary venules.
Reaction develops rapidly after antigen exposure because of preformed antibody
Test: skin tests for specific IgE
Disorders: anaphylaxis (bee sting, food allergies), hives, eczema, hay fever
ACID: Anaphylactic and atopic (type 1) Cytotoxic (type 2) Immune complex (type 3) Delayed cell mediated (type 4)
Hypersensitivity type 2
IgM, IgG bind to fixed antigen on “enemy” cell, leading to cellular destruction
3 mechanisms:
Opsonization leading to phagocytosis or complement activation
Complement mediated lysis
Antibody dependent cell-mediated cytotoxicity, usually due to NK cells or macrophages
Tests:
Direct Coombs: detects antibodies on RBCs (use antihuman antibodies)
Indirect Coombs: detects antigens that can lead to antibody binding on RBCs(use anti RBC antigen antibodies followed by antihuman antibodies)
Disorders: autoimmune hemolytic anemia, pernicious anemia, ITP, bullous pemphigoid, rheumatic fever
Hypersensitivity type 3
Antigen-antibody (IgG) complexes activate complements, which attracts neutrophils, neutrophils release lysosomal enzymes
Test: immunoflurorescent staining
Disorders: SLE, Serum sickness, arthus reaction, post-strep glomeruloneprhitis
Hypersensitivity type 4
Sensitized T lymphocytes encounter antigen and then release lymphokines, which lead to macrophage activation
NO antibodies involved
Test: patch test, PPD
Disorders: multiple sclerosis, Guillian-Barre syndrome, graft vs host disease, contact dermatitis
Blood transfusion reactions
Allergic reaction: type I against plasma proteins, urticaria, fever, treat w/ antihistamines
Anaphylactic reaction: severe allergic reaction, dyspnea, respiratory arrest, shock
Febrile nonhemolytic transfusion reaction: type 2, host antibodies against donor HLA antigens and leukocytes, fever, headaches, flushing
Acute hemolytic transfusion reaction: type 2, intravascular hemolysis or extravascular hemolysis (against foreign antigen on donor RBCs), fever, hemoglobinemia, jaundice
X-linked agammaglobulinemia
B cell disorder (Bruton), X linked recessive
Defect in BTK, no B cell maturation
Recurrent bacterial and enteroviral infections
Normal B cell count, decreased Ig of all classes
Selective IgA deficiency
B cell disorder
Most common primary immunodeficiency
Majority asymptomatic, can have airway and GI infections and anaphylaxis to IgA containing products
Low IgA w normal IgG and IgM
Common variable immunodeficiency
B cell disorder
Defect in B cell differentiation
Increase risk of autoimmune disorders, bronchiectasis, lymphoma
Decreased plasma cells and decreased immunoglobulins (all)
Thymic aplasia (Digeorge)
T cell disorder
22q11 deletion, failure to develop thymus
Recurrent viral/fungal infections
Decreased T cells, absent thymic shadow on CXR
IL12 receptor deficiency
T cell disorder
Decreased Th1 response
Disseminated myobacterial and fungal infections
Decreased IFNgamma
Autosomal dominant IgE syndrome
T cell disorder
Deficiency of Th17, impaired recruitment of neutrophils
Coarse facies, abscesses, eczema
Increased IgE, decreased IFNgamma
Chronic mucocutaneous candidasis
T cell disorder
T cell dysfunction
Noninvasive Candida infection of skin and mucus membranes
Absent T-cell proliferation in response to Candida
Severe combined immunodeficiency (SCID)
Both B and T
Adenosoine deaminase deficiency (decreased lymphocyte proliferation due to lack of DNA synthesis)
Failure to thrive, chronic diarrhea, recurrent infections
Decreased lymphocyte count
Treatment: bone marrow transplant
Ataxia-telangiectasia
Both B and T
Lack of double strand repair leading to cell cycle arrest
Cerebellar defect, spider angiomas, IgA deficiency
Increased AFP, decreased Ig
Hyper IgM
Both B and T
CD40 ligand defect –> class switching defect
Severe pyogenic infections, opportunistic infecdtions
Increased IgM, close to zero for other Ig
Wiskott-Aldrich syndrome
Both B and T
WAS gene mutation, T cells unable to reorganize actin cytoskeleton
Thrombocytopenia purpura, Eczema, Recurrent infections
Decreased IgG, IgM, increased IgE, IgA
Leukocyte adhesion deficiency
Defect in integrin on phagocyte, impaired migration and chemostasis
Recurrent bacterial skin and mucosal infection, impaired wound healing, delayed separation of umbilical cord
Increased neutrophils but absent at infection site
Chediak-Higashi syndrome
Defect in lysosomal trafficking regulator, microtubule dysfunction in phagosome-lysosome fusion
Recurrent infections, progressive neurodegeneration
Giant granules in neutrophils and platelets
Chronic granulomatous disease
Defect of NADPH oxidase, decreased reactive oxygen species available for respiratory burst in neutrophils
Susceptibility to catalase positive organisms
Abnormal dihydrorhodamine (can be normally oxidized and produce fluorescence if tagged) test
Hyperacute transplant rejection
Within minutes
Type 2 reaction due to pre-existing antibodies to donor antigen
Widespread thrombosis of graft vessels, graft must be removed
Acute transplant rejection
Weeks to months
Cellular: Tc activated against donor MHCs (seen as foreign)
Humoral: type 2, but antibodies develop later
Vasculitis of graft vessels, prevent/reverse w/ immunosuppressants
Chronic transplant rejection
Months to years
Recipient T cells perceive donor MHC as recipient MHC but react against donor antigens presented. Both cellular and humoral
Irreversible damage such as atherosclerosis and vanishing bile ducts
Graft vs host disease
Grated immunocompetent T cells proliferate in the immunocompromised host and reject host cells w/ “foreign” proteins –> severe organ dysfunctions
Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly
Usually in bone marrow and liver transplants
Potentially beneficial in bone marrow transplant for leukemia (graft vs tumor effect)
Cyclosporine
Calcineurin inhibitor: binds T cell activation by preventing IL2 transcription
Used for transplant rejection prophylaxis and RA
Nephrotoxicity, hypertension, hyperlipidemia, hyperglycemia, gingival hyperplasia
Tacrolimus
Calcineurin inhibitor: blocks T cell activation by preventing IL 2 transcription
Used for transplant rejection prophylaxis
Nephrotoxicity, increased risk of diabetes and neurotoxicity
Sirolimus
mTOR inhibitor: blocks T cell activation and B cell differentiation by preventing IL2 signal transduction
Kidney transplant rejection prophylaxis
Causes anemia, leukopenia, thrombocytopenia, NOT nephrotoxic
Basiliximab
Monocolonal antibody blocking IL2 receptor
Kidney transplant rejection prophylaxis
Edema, hypertension
Azathioprine
Inhibits lymphocyte proliferation by blocking nucleotide synthesis (blocking 6-MP)
Transplant rejection prophylaxis, RA, Crohns, glomerulonephritis
Anemia, leukopenia, thrombocytopenia
Glucocorticoids
Inhibit NFkB, suppresses both B and T cell function by decreased transcription of cytokines
Transplant rejection prophylaxis, autoimmune disorders
Hyperglycemia, osteoporosis, central obesity, muscle breakdown, iatrogenic Cushing syndrome
Epoetin alfa
Erythropoietin
Used to treat anemias especially in renal failure
Filgrastim/Sargramostim
Granulocyte/macrophage colony stimulating factor
Recovery of bone marrow
Oprelvekin
Thrombopoietin
Used to treat thrombocytopenia
Alemtuzumab
Target CD52 to treat CLL
Bevacizumab
Target VEGF to treat colorectal and renal cell cancer
Cetuximab
Target EGFR to treat colorectal, head and neck cancer
Rituximab
Target CD20 to treat B cell non-Hodgkin lymphoma, RA, ITP
Trastuzumab
Target HER2 to treat breast cancer
Infliximab
Target TNFalpha to treat IBD, RA, and psoriasis
Natalizumab
Target alpha4 integrin to treat multiple sclerosis and Crohns, can cause PML in MS patients w/ JC virus
Abciximab
Target glycoprotein IIb/IIIa as anti platelet agent to prevent ischemic complications
Palivizumab
Target RSV F protein as prophylaxis for high risk infants
Denosumab
Target RANKLigand (control bone remodeling) for osteoporosis by inhibiting osteoclast maturation
Omalizumab
Target IgE for allergic asthma
