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Immunology Flashcards

1
Q

Lymph node

A

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

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2
Q

Lymph node follicle

A

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

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3
Q

Medulla

A

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

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4
Q

Paracortex

A

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

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5
Q

Lymph drainage

A

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

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6
Q

Sinusoids of spleen

A

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

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7
Q

Thymus

A

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

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8
Q

Innate immunity

A

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)

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9
Q

Adaptive immunity

A

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

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10
Q

MHC I

A

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

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11
Q

MHC II

A

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

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12
Q

Natural killer cells

A

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)

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13
Q

B cell functions

A

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

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14
Q

T cell functions

A

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

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15
Q

T cell differentiation

A

Bone marrow: T cell precursors synthesized

Thymus cortex: positive selection

Thymus medulla: negative selection

Lymph node: Tc cells and Th cells are distributed

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16
Q

Positive selection

A

Thymic cortex

T cells expressing TCRs capable of binding self MHC molecules survive

Apoptosis in T cells unable to recognize

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17
Q

Negative selection

A

Thymic medullar

T cells expressing TCRs with high affinity for self-antigens undergoes apoptosis

Remaining cells survive

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18
Q

Naive T cell activation

A
  1. Foreign body is phagocytksed by dendritic cell
  2. Foreign antigen is presented on MHCII and recognized by TCR on Th cell. Antigen presented on MHCI to Tc cells
  3. Costimulatory signal is then given by interaction of B7 (from dendritic cell) and CD28 (T cells) after MHC/TCR binding
  4. Th cell activates and produce cytokines
  5. Tc cells activates and is able to recognize and kill virus infected cells
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19
Q

B cell activation and class switching

A
  1. Th cell activation
  2. B cell receptor-mediated endocytosis, foreign antigen is presented on MHCII and recognized by TCR on Th cell
  3. Costimulatory signal is given by CD40 ligand (Th cell) interaction w/ CD40 of B cell after MHC/TCR binding
  4. Th cell secrets cytokines that determines Ig class switching of B cell.
  5. B cell activates and undergoes class switching, affinity maturation, and antibody production
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20
Q

Th1 cells

A

Secrete IFNgamma

Activates macrophages and Tc cells

Inhibited by IL4 (secreted from Th2 cells) and IL10 (secreted from Tregs)

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21
Q

Th2 cells

A

Secrete IL4, IL5, IL6

Recruits eosinophils for parasite defense

Promotes IgE production by B cells

Inhibited by IFNgamma (secreted by Th1)

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22
Q

Macrophage-lymphocyte interaction

A

Macrophages release IL12, which stimulates T cells to differentiate into Th1 cells

Th1 cells release IFNgamma to stimulate macrophages

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23
Q

Tc cells

A

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)

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24
Q

Regulatory T cells (special Th2 cells)

A

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

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25
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
26
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)
27
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)
28
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
29
IgD
Unclear function Found on surface of many B cells and in serum
30
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
31
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
32
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
33
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
34
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
35
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
36
Complement inhibition
Decay-accelerating factor (DAF/CD55), C1 esterase inhibitor Prevent complement activation on self cells (RBCs)
37
C1 esterase inhibitor deficiency
Hereditary angioedema (inflammation 2ndary to lack of inhibition of complements) ACE inhibitors are contraindicated
38
C3 deficiency
Increase risk of severe, recurrent pyogenic sinus and respiratory tract infections Increased susceptibility to typeIII hypersensitivity
39
C5-C9 deficiency
Increase susceptibility to recurrent Neisseria bacterimia
40
DAF deficiency
Complement mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria
41
IL1
Secreted by macrophages Endogenous pyrogen, causes fever and acute inflammation Induces chemokine secretion to recruit leukocytes
42
IL2
Secreted by all T cells Stimulate growth of ALL T cells
43
IL3
Secreted by all T cells Suppor the growth and differentiation of bone marrow stem cells into lymphoid and myeloid progenitors
44
IL4
Secreted from Th2 cells Induce differentiation into Th2 cells Promote growth of B cells Enhances class switching to IgE and IgG
45
IL5
Secreted by Th2 cells Promote differentiation of B cells Enhances class switching to IgA Stimulate growths and differentiation of eosinophils
46
IL6
Secreted by macrophages Causes fever and stimulate production of acute phase proteins
47
IL8
Secreted by macrophages Major chemotactic factor for neutrophils, neutrophils are recruited to clear infections
48
IL12
Secreted by macrophages Induce differentiation of T cells into Th1 cells Activates NK cells
49
TNFalpha
Secreted by macrophages Mediates septic shock Activates endothelium causing leukocyte recruitment and vascular leak
50
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
51
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
52
Anergy
Self-reactive T cells become nonreactive without costimulatory molecule
53
Passive immunity
Receiving preformed antibodies Rapid onset Short life span of antibodies IgA in breast milk, maternal IgG crossing placenta, humanized monoclonal antibodies injected
54
Active immunity
Exposure to foreign antigen Slow onset Long lasting protection (memory) Natural infection, vaccination
55
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) ```
56
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
57
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
58
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
59
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
60
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
61
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
62
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)
63
Thymic aplasia (Digeorge)
T cell disorder 22q11 deletion, failure to develop thymus Recurrent viral/fungal infections Decreased T cells, absent thymic shadow on CXR
64
IL12 receptor deficiency
T cell disorder Decreased Th1 response Disseminated myobacterial and fungal infections Decreased IFNgamma
65
Autosomal dominant IgE syndrome
T cell disorder Deficiency of Th17, impaired recruitment of neutrophils Coarse facies, abscesses, eczema Increased IgE, decreased IFNgamma
66
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
67
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
68
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
69
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
70
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
71
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
72
Chediak-Higashi syndrome
Defect in lysosomal trafficking regulator, microtubule dysfunction in phagosome-lysosome fusion Recurrent infections, progressive neurodegeneration Giant granules in neutrophils and platelets
73
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
74
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
75
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
76
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
77
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)
78
Cyclosporine
Calcineurin inhibitor: binds T cell activation by preventing IL2 transcription Used for transplant rejection prophylaxis and RA Nephrotoxicity, hypertension, hyperlipidemia, hyperglycemia, gingival hyperplasia
79
Tacrolimus
Calcineurin inhibitor: blocks T cell activation by preventing IL 2 transcription Used for transplant rejection prophylaxis Nephrotoxicity, increased risk of diabetes and neurotoxicity
80
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
81
Basiliximab
Monocolonal antibody blocking IL2 receptor Kidney transplant rejection prophylaxis Edema, hypertension
82
Azathioprine
Inhibits lymphocyte proliferation by blocking nucleotide synthesis (blocking 6-MP) Transplant rejection prophylaxis, RA, Crohns, glomerulonephritis Anemia, leukopenia, thrombocytopenia
83
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
84
Epoetin alfa
Erythropoietin Used to treat anemias especially in renal failure
85
Filgrastim/Sargramostim
Granulocyte/macrophage colony stimulating factor Recovery of bone marrow
86
Oprelvekin
Thrombopoietin Used to treat thrombocytopenia
87
Alemtuzumab
Target CD52 to treat CLL
88
Bevacizumab
Target VEGF to treat colorectal and renal cell cancer
89
Cetuximab
Target EGFR to treat colorectal, head and neck cancer
90
Rituximab
Target CD20 to treat B cell non-Hodgkin lymphoma, RA, ITP
91
Trastuzumab
Target HER2 to treat breast cancer
92
Infliximab
Target TNFalpha to treat IBD, RA, and psoriasis
93
Natalizumab
Target alpha4 integrin to treat multiple sclerosis and Crohns, can cause PML in MS patients w/ JC virus
94
Abciximab
Target glycoprotein IIb/IIIa as anti platelet agent to prevent ischemic complications
95
Palivizumab
Target RSV F protein as prophylaxis for high risk infants
96
Denosumab
Target RANKLigand (control bone remodeling) for osteoporosis by inhibiting osteoclast maturation
97
Omalizumab
Target IgE for allergic asthma

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