zimmunology Flashcards
1
Q
Lymph node
A
- a 2’ lymphoid organ that has many afferents, 1 or more efferents.
- encapsulated, with trabeculae
- functions are nonspecific filtration by macrophages, storage, activation of B & T cells, antibody production
2
Q
Follicle
A
- site of B cell localization and proliferation
- in outer cortex
- 1’ follicles are dense and dormant
- 2’ follicles have pale central germinall centers and are active
3
Q
medulla
A
- consists of medullary cords (closely packed lymphocytes and plasma cells) and meduallary sinuses
- medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages
4
Q
paracortex
A
houses T cells
- region of cortex btw follicles and medulla
- contains high endothelial venules through which T and B cells enter from blood
- In an extreme cellular immune response, paracortex becomes greatly enlarged
- not well developed in pts with DiGeorge syndrome
- paracortex enlarges in an extreme cellular immune re5sponse
5
Q
lymph drainage: area of body & 1’ lumph node drainage site
- upper limb, lateral breast
- stomach
- duodenum, jejunum
- sigmoid colon
- rectum (lower portion) of anal canal (above pectinate line)
- anal canal (below pectinate line)
- testes
- scrotum
- thigh (superficial)
- lateral side of dorsum of foot
A
- axillary
- celiac
- superior mesenteric
- colic–>inferior mesenteric
- internal iliac
- superficial inguinal
- superficial & deep plexuses–>para-aortic
- superficial inguinal
- superficial inguinal
- popliteal
* **right lymphatic duct–drains right arm, right chest, right half of head, thoracic duct drains everything else
6
Q
sinusoids of spleen
A
- long vascular channels in red pulp with fenestrated “barrel hoop” basement membrane
- macrophages found nearby
- T cells are found in periarterial lymphatic sheath (PALS) w/in white pulp of the spleen
- B cells found in follicles w/in white pulp of spleen
- macrophages in spleen remove encapsulated bact
- splenic dysfunction: dec IgM–>dec complement activation–>dec C3b opsonization–>inc susceptibility to encapsulated organisms:
1. streptococcus pneumoniae
2. Haemophilus influenzae type B
3. Neisseria meningitidis
4. Salmonella
5. Klebsiella pneumoniae
6. group B streptococci (SHiN SKiS) - postplencectomy:
1. Howell-JOlly bodies (nuclear remnants)
2. target cells
3. thrombocytosis
7
Q
thymus
A
- site of T cell differentiation and maturation
- encapsulated
- from epithelial of 3rd branchial puches
- lymphocytes of mesenchymal origin
- cortex is dense with immature T cells; medulla is pale with mature T cells and epithelial reticualr cells containing Hassal’s corpuscles
- positive selection (MHC restriction) occurs in the cortex and negative selection (nonreactive to self) occurs in the medulla
- T cells=thymus
- Bcell=bone marrow
8
Q
innate vs adaptive immunity
A
innate
- receptors that recognize pathogens are germline encoded
- response to pathogens is fast and nonspecific
- no memory
- consists of neutrophils, macrophages, dendritic cells, natural killer cells (lymphoid origin) and complement
adaptive:
- receptors that recognize pathogens undergo V(D)J recombination during lymphocyte development
- response is slow on first exposure, but memory response is faster and more robust
- consists of T cells, B cells, and circulating antibody
9
Q
What is MHC
A
-major histocompatibility complex, encoded by human leukocyte antigen (HLA) genes; present antigen fragments to T cells and bind TCR
10
Q
MHCI
A
- HLA-A, HLA-B, HLA-C
- binds TCR and CD8
- expressed on all nucleated cells. not expressed on RBC
- antigen is loaded in RER with mostly intracellular peptides
- mediates viral immunity
- pairs with beta2-microglobulin (aids in transport to cell surface)
11
Q
MHC-II
A
HLA_DR, HLA-DP, HLA-DQ
- binds TCR and CD4
- expressed only on antigen-presenting cells (APCs)
- antigen is loaded following release of invariant chain in an acidified endosome
12
Q
HLA subtype associated with dz:
- A3
- B27
- DQ2/DQ8
- DR2
- DR3
- DR4
- DR5
A
- hemochromatosis
- psoriasis, Ankylosing spondylitis, inflammatory bowel dz, Reiter’s syndrome (PAIR)
- celiac dz
- multiple sclerosis, hay fever, SLE, Goodpasture’s
- diabetes mellitus type 1, Graves’ disease
- Rheumatoid arthritis, diabetes mellitus type 1
- pernicious anemia–>B12 deficiency, Hashimoto’s thyroiditis
13
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 IL-2, IL-12, IFN-beta, IFN-alpha
- 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
14
Q
B cell functions
A
- make antibody–opsonize bact, neutralize viruses (IgG)
- activate complement (IgM, IgG)
- sensitize mast cells (IgE)
- allergy (type I hypersensitivity): IgE
- cytotoxic (type II) and immune complex (type III) hypersensitivity: IgG
- hyperacute and humorally mediated acute and chronic organ rejection
15
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 IV)
- acute and chronic cellular organ rejection
16
Q
Differentiation of T cells:
- positive selection
- negative selection
A
- thymic cortex. T cells expressing TCRs capable of binding surface self MHC molecules survive
- Medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis
17
Q
T & B cell activation
A
- antigen-presenting cells (APCs)
- dendritic cells (only APC that can activate naive T cell)
- macrophage
- B cell
- two signals are required for T cell activation and B cell activation and class switching
18
Q
naive T cell activation
A
- foreign body is phagocytosed by dendritic cell
- foreign antigen is presented on MHC II and recognized by TCR on Th (helper) cell. Antigen is presented on MHC I to Tc (cytotoxic) cells (signal 1)
- Costimulatory signal is given by interaction of B7 and CD28 (signal 2)
- Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus-infected cell
19
Q
B cell activation and class switching
A
- Helper T cell activation as above
- B cell receptor-mediated endocytosis; foreign antigen is presented on MHC II and recognized by TCR on Th cell (signal 1)
- CD40 receptor on B cell binds CD40 ligand on Th cell (signal 2)
- Th cell secreted cytokines that determine Ig class switching of B cell. B cell activates and undergoes class switching, affinity maturation, and antibody production
20
Q
Helper T cells: Th1 cell vs. Th2 cells
A
Th1 cell
- secretes IFN-gamma
- activates macrophages
- inhibited by IL-4, IL-10 (from Th2 cell)
Th2 cell
- secretes IL-4, IL-5, IL-10, IL-13
- recruits eosinophils for parasite defense and promotes IgE production by B cells
- inhibited by IFN-gamma (from Th1 cell)
- macrophage-lymphocyte interaction–activated lymphocytes (release IFN-gamma) and macrophages (release IL-1, TNF-alpha) stimulate one another
- helper T cells have CD4, which binds to MHC II and APCs
21
Q
cytotoxic T cells
A
- kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis
- release cytotoxic granules containing preformed proteins
- perforin–helps to deliver the content of granules into target cell;
- granzyme–a serine protease, activates apoptosis inside target cell
- granulysin–antimicrobial, induces apoptosis
- cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells
22
Q
regulatory T cells
A
- help maintain specific immune tolerance by suppressing CD4 & CD8 T cell effector function
- express CD3, CD4, CD25 (alpha chain of IL-2 receptor) cell surface markers
- activated regulatory T cells produce anti-inflammatory cytokines like IL-10 and TGF-beta
23
Q
antibody structure and function:
A
- variable part of L & H chains recognizes antigens
- Fc portion of IgM & IgG fixes complement
- heavy chain contributes to Fc & Fab fractions
- light chain contributes only to Fab fraction
24
Q
Fab antibody region
A
- antigen-binding fragment
- determines idiotype: unique antigen-binding pocket; only 1 antigenic specificity expressed per B cell
25
Q
Fc antibody region
A
- constant
- carboxy terminal
- complement binding at CH2 (IgG + IgM only)
- carbohydrate side chains
- determine isotype (IgM, IgD, etc)
26
Q
antibody diversity is generated by:
A
- random recombination of VJ (light chain) or V(D)J (heavy chain) genes
- random combination of heavy chains with light chains
- somatic hypermutation (following antigen stimulation)
- addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase
27
Q
immunoglobulin isotypes
A
- mature B lymphocytes express IgM & IgD on their surfaces
- they may differentiate by isotype switching (gene rearrangement; mediated by cytokines and CD40 ligand) into plasma cells that secretes IgA, IgE, IgG
28
Q
IgG isotype
A
- main antibody in 2’ (delayed) response to an antigen
- most abundant isotype
- fixes complement, crosses placenta (provides infants with passive immunity), opsonization bact, neutralizes bact toxins and viruses
29
Q
IgA
A
- prevents attachment of bact & viruses to mucous membrane
- does not fix complement
- monomer (in circulation) or dimer (when secreted)
- crosses epithelial cells by transcytosis
- found in secretion—tears, saliva, mucus, and early breast milk (colostrum)
- picks up secretory component from epithelial cells before secretion
30
Q
IgM
A
- produced in the 1’ (immediate) response to an antigen
- fixes complement but does not cross the placenta
- antigen receptor on the surface of B cells
- monomer on B cell or pentamer
- shape of pentamer allows it to efficiently trap free antigens out of tissue while humoral response evolves
31
Q
IgD
A
- unclear function
- found on the surface of many B cells and in serum
32
Q
IgE
A
- binds mast cells and basophils; cross links when exposed to allergen, mediating immediate (typeI) hypersensitivity through release of inflammatory mediators such as histamine
- mediate immmunity to worms by activiating eosinophils
- lowest concentratoin in serum
33
Q
antigen type & memory
- thymus-independent antigen
- thymus-dependent antigen
A
- antigens lacking peptide component; cannot be presented by MHC to T cells (eg. lipopolysaccharide from cell envelope of gram-neg bacteria and polysaccharide capsular antigen). Stimulate release of antibodies and do not result in immunologic memory
- antigens containing a protein component (eg. diphtheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40 ligand interaction)
34
Q
complement: Overview Activation Functions Opsonins inhibitor
A
Overview
- system of interacting proteins that play a role in innate immunity and inflammation
- membrane attack complex (MAC) of complement defends against gram-neg bact
Activation
- classic pathway–IgG or IgM mediated
- alternative pathway–microbe surface molecules
- Lectin pathway–mannose or other sugars on microbe surface
- GM makes classic cars
Functions
- C3b–opsonization
- C3a, C5a–anaphylaxis
- C5a–neutrophil chemotaxis
- C5b-9 cytolysis by MAC
- C3b binds bact
Opsonins
-C3b and IgG are the two 1’ opsonins in bacterial defense; C3b also helps clear immune complexes
Inhibitor
-decay-accelerating actor (DAF) and C1 esterase inhibitor help prevent complement activation on self cells (eg. RBC)
35
Q
Complement disorders
- C1 esterase inhibitor deficiency
- C3 deficiency
- C5-C9 deficiencies
- DAF (GPI anchored enzyme) deficiency
A
- hereditary angioedema. ACE inhibitors are contraindicated
- severe, recurrent pyogenic sinus and respiratory tract infections; increase susceptibility to type III hypersensitivity rxns
- recurrent Neisseria bacteremia
- complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria (PNH)
36
Q
Cytokines secredted by: macrophages
- 5 types
- description
A
IL-1
- an endogenous pyrogen
- causes fever, acute inflammation
- activates endothelium to express adhesion molecules
- induces chemokine secretion to recruit leukocytes
IL6
- an endogenous pyrogen
- also secreted by Th2 cells
- causes fever and stimulates production of acute-phase proteins
IL8
- major chemotactic factor for neutrophils
- clean up on aisle 8. Neutrophils are recruited by IL8 to clear infections
IL12
- induces differentiation of T cells into Th1 cells
- activates NK cells
- also secreted by B cells
TNF-alpha
- mediates septic shock
- activates endothelium
- causes leukocytes recruitment, vascular leak
37
Q
Hot T-bone stEAk:
IL1-5 stimulates?
A
IL-1: fever (hot) IL2-stimulates T cells IL3-stimulates Bone marrow IL4-stimulates IgE production IL5-stimulates IgA production
38
Q
Cytokines secreted by: all T cells
- 2 types
- description
A
IL2
-stimulates growth of helper, cytotoxic, and regulatory T cells
IL3
- supports the growth and differentiation of bone marrow stem cells
- functions like GM-CSF
39
Q
Cytokines secreted by: Th1 cells
- one type
- description
A
Interferon-gamma
- activates macrophages and Th1 cells
- suppresses Th2 cells
- has antiviral and antitumor properties
40
Q
Cytokines secreted by: Th2 cells
- 3 types
- description
A
IL4
- induces differentiation into Th2 cells
- prmotes growth of B cells. Enhances class switching to IgE and IgG
IL5
- promotes differentiation of B cells
- enhances class switching to IgA
- stimulates the growth and differentiation of eosinophils
IL10
- modulates inflammatory response
- inhibits actions of activated T cells and Th1
- also secreted by regulatory T cells
- TGF-beta has similar actions to IL-10, because it is involved in inhibiting inflammation
41
Q
interferon mechanism
A
- interferons (alpha, beta, gamma) are proteins that place uninfected cells in an antiviral state
- interferons induce the production of a ribonuclease that inhibits viral protein synthesis by degrading viral mRNA (but not hose mRNA)
- interferes with viruses:
1. alpha & beta interferons inhibit viral protein synthesis
2. gamma interferons increase MHC I and II expression and antigen presentation in all cells. activates NK cells to kill virus-infected cells
42
Q
cell surface proteins
- T cells
- Helper T cells
- Cytotoxic cells
- B cells
- macropphages
- NK cells
A
all cells except mature RBCs have MHC I
- T cells
- TCR (binds antigen-MHC complex)
- CD3 (associated c TCR for signal transduction)
- CD28 (binds B7 on APC) - Helper T cells–>CD4, CD40 ligand
- Cytotoxic cells–>CD8
- B cells
- Ig (bind antigen)
- CD19, CD20, CD21 (receptor for EBV), CD40
- MHC II, B7
- you can drink beer at the bar when you’re 21: B cells, Epstein-Barr virus; CD-21 - macropphages
- CD14, CD40
- MHC II, B7
- Fc & C3b receptors (enhanced phagocytosis) - NK cells
- CD16 (binds Fc of IgE), CD56 (unique marker for NK)
43
Q
Anergy
A
- self-reactive T cells become nonreactive w/o costimulatory molecule
- B cells also become anergic, but tolerance is less complete than in T cells
44
Q
Effects of bacterial toxins
A
- superantigens (S. pyogenes & S. aureus)–cross link the beta region of the T-cell receptor to the MHC class II on APCs
- can activate any T cell, leading to massive release of cytokines
- endotoxins/liposaccharide (gram neg bact)–directly stimulate macrophages by binding to endotoxin receptor CD14; Th cells are not involved
45
Q
antigen variation classic eg.
A
- bact–Salmonella (2 flagellar variants), Borrelia (relapsing fever), Neisseria gonorrhoeae (pilus protein)
- virus–influenza (major=shift, minor=drift)
- parasites—trypanosomes (programmed rearrangement)
-some mechanisms for variation include DNA rearrangement and RNA segment reassortment (eg. influenza major shift)
46
Q
Passive immunity
- means of acquisition
- onset
- duration
- examples
- notes
A
- receiving preformed antibodies
- rapid
- short span of antibodies (half-life=3wks)
- IgA in breast milk, antitoxin, humanized monoclonal antibody
- after exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive)—To Be Healed Rapidly
47
Q
Active immunity
- means of acquisition
- onset
- duration
- examples
- notes
A
- exposure to foreign antigens
- slow
- long lasting protection (memory)
- natural infection, vaccines, toxoid
- combined passive and active immunizations can be given in case of hepatitis B or rabies exposure
48
Q
overview of vaccination
A
-vaccines are used to induce an active immune response (humoral and/or cellular) to specific pathogens
49
Q
live attenuated vaccine
- description
- Pros/Cons
- Examples
A
1.description
-microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Mainly induces a cellular response
2.Pros–induces strong, often life long immunity
Con–may revert to virulent form
3.Examples
-Measles, mumps, polio (Sabin), rubella, varicella, yellow fever
50
Q
Inactivated or killed vaccine
- description
- Pros/Cons
- Examples
A
1.description
-pathogen is inactivated by heat or chemicals; maintaining epitope structure on surface antigen is important for immune response. Hummoral immunity induced
2.Pros–stable and safer than live vaccines
Cons—weaker immune response; booster shots usually required
3.Examples
-cholera, hepatitis A, Polio (Salk), rabies
51
Q
Hypersensitivity Type: 1
A
- anaphylactic and atopic–free antigen cross-links IgE on presensitized mast cells and basophils, triggering release of vasoactive amines that act at postcapillary venules (i.e. histamine)
- reaction develops rapidly after antigen exposure because of preformed antibody
- First (type) and Fast (anaphylaxis). Types 1, 2, 3 are all antibody mediated. test: skin test for specific IgE
52
Q
Hypersensitivity Type: 2
A
- cytotoxic (antibody mediated)–IgM, IgG bind to fixed antigen on enemy cell, leading to cellular destruction
- 3 mechanisms:
1. opsonization leading to phagocytosis or complement activation
2. complement-mediated lysis
3. Antibody-dependent cell-mediated cytotoxicity (ADCC) usually due to NK cells - **Type 2 is cy-2-toxic
- antibody and complement lead to membrane attack complex (MAC)
- test: direct and indirect Coombs’
53
Q
Hypersensitivity Type: 3
- serum sickness
- arthus reaction
A
- immune complex–antigen-antibody (IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes
- in type III reaction, imagine an immune complex as 3 things stuck together: antigen-antibody-complement
- serum sickness
- an immune complex dz (type III) in which antibodies to the foreign proteins are produced (takes 5 days)
- immune complexes form and are deposited in membranes, where they fix complement (leads to tissue damage)
- more common than Arthus rxn
- most serum sickness now caused by drugs (not serum) acting as haptens. Fever, urticaria, arthralgias, proteinuria, lymphadenopathy 5-10 days after antigen exposure
2.arthus reaction
-a local subacute antibody-mediated hypersensitivity (type III) rxn
-intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin
-characterized by edema, necrosis, activation of complement
**antigen-antibody complexes cause the Arthus rxn,
Test: immunnofluorescent staining
54
Q
Hypersensitivity Type: 4
A
-delayed (T-cell mediated) type–sensitized T lymphocytes encounter antigen and then release lymphokines (leads to macrophage activation; no antibody involved)
-4th and last–delayed. Cell mediated; thereore, not transerferable by serum
-4Ts= T lymphocytes, Transplant rejections, TB skin tests, Touching (contact dermatitis)
-Test: patch test, PPD
-ACID
Anaphylactic and Atopic (type I)
Cytotoxic (antibody-mediated) type II
Immune complex type III
Delayed (cell mediated) type IV
55
Q
Hypersensitivity disorders: type I
- Examples
- presentation
A
- anaphylaxis (bee sting, some food/drug allergies).
- allergic an datopic disorders (rhinitis, hay fever, eczema, hives, asthama)
2.immediate, anaphylactic, atopic
56
Q
Hypersensitivity disorders: type II
- Examples
- presentation
A
- autoimmune hemolytic anemia (AIHA)
- pernicious anemia
- idiopathic thrombocytopenic purpura
- erythroblastosis fetalis
- acute hemolytic transfusion rxn
- rheumatic fever
- goodpasture’s syndrome
- bullous pemphigoid
- pemphigus vulgaris
2.dz tends to be specific to tissue or site where antigen is found
57
Q
Hypersensitivity disorders: type III
- Examples
- presentation
A
1.SLE
-Polyarteritis nodosa
-poststreptococcal glomerulonephritis
-serum sickness
-arthus rnx (eg swelling and inflammation following tetanus vaccine)
-
2.can be associated with vasculitis and systemic manifestation
58
Q
Hypersensitivity disorders: type IV
- Examples
- presentation
A
- Multiple sclerosis
- Guillain-Barre syndrome
- Graft vs host disease
- PPD (test for M tuberculosis)
- contact dermatitis (eg poison ivy, nickle allergy)
2.response is delayed and does not involve antibodies (vs. type I, II, III)
59
Q
blood transfusion rnx: pathogens & presentation
- allergic rnx
- anaphylactic rnx
- febrile nonhemolytic transfusion rnx (FNHTR)
- Acute hemolytic transfusion rnx (HTR
A
- allergic rnx
- type I hypersensitivity rnx against plasma proteins in transfused blood
- urticaria, pruritus, wheezing, fever, treat with antihistamines - anaphylactic rnx
- severe rnx; IgA-deficient individuals must receive blood produts that lack IgA
- dyspnea, bronchospasm, hypotension, respiratory arrrest, shock - febrile nonhemolytic transfusion rnx (FNHTR)
- type II hypersensitivity rnx. host antibodies against donor HLA antigens and leukocytes
- fever, HA, chills, flushing - Acute hemolytic transfusion rnx (HTR
- type II hypersensitivity rnx; intracellular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody rnx against foreign antigen on donor RBCs)
- fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinemia (intravascular), jaundice (extravascular hemolysis)
60
Q
Autoantibodies & associated disorder
- Antinuclear antibodies (ANA)
- anti-dsDNA, anti-Smith
- antihistone
- rheumatoid factor, anti-CCP
- anticentromere
- anti-Scl-70 (anti-DNA topoisonmerase I)
- antimitochondrial
- IgA antiendomysial, IgA anti-tissue transglutaminase
- anti-basement membrane
- anti-desmoglein
- antimicrosomal, antithyroglobulin
- anti-Jo-1, anti-SRP, anti-Mi-2
- anti-SSA (anti-Ro)
- anti-U1 RNP (ribonucleoprotein)
- anti-smooth muscle
- anti-glutamate decarboxylase
- c-ANCA (PR3-ANCA)
- p-ANCA (MPO-ANCA)
- anti-SSB (anti-La
A
- SLE, nonspecific
- SLE
- drug-induced lupus
- rheumatoid arthritis
- scleroderma (CREST syndrome)
- scleroderma (diffuse)
- 1’ billary cirrhosis
- celiac disease
- Goodpasteur’s syndrome
- Pemphigus vulgaris
- Hashimoto’s thyroiditis
- Polymyositis, dermatomyositis
- Sjogren’s syndrome
- mixed connective tissue disease
- autoimmune hepatitis
- type 1 DM
- granulomatosis with polyangiitis (Wegener’s)
- microscropic polyangiitis, Churg-strauss syndrome
- Sjogren’s syndrome
61
Q
Infections in immunodeficiency: bacteria, virus, fungi/parasites
- Pathogen,
- No T cells,
- No B cells,
- No granulocyte
- No complement
A
Bacteria:
- No T cells–>sepsis
- No B cells–>encapsulated: Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitidis, Salmonella, Klebsiella pneumoniae, group B Strep (SHiN SKiS)
- No granulocyte–>Staphylococcus, Burkholderia cepacia, Serratia, Nocardia
- No complement–>Neiserria (no membrane attack complex)
Virus:
- No T cells–>CMV, EBV, VZV, chronic infection with respiratory/GI viruses
- No B cells–>enteroviral encephalitis, poliovirus (live vaccine contraindicated)
- No granulocyte–>N/A
- No complement–>N/A
Fungi/parasites
- No T cells–>Candida, PCP
- No B cells–>GI giardiasis (no IgA)
- No granulocyte–>Candida, Aspergillus
- No complement–>N/A
** B cell deficiencies tend to produce recurrent bacterial infections, whereas T cell deficiencies produce more fungal and viral infections
62
Q
Immune deficiencies:B cell disorders
- 3 types
- defect
- presentation
- findings
A
X-linked (Bruton’s) agammaglobulinemia
- defect
- X-linked recessive (inc in Boys). Defect in BTK, a tyrosine kinase gene–>no B cell maturation - presentation
- recurrent bacterial infections after 6 months (decrease maternal IgG) as a result of opsonization defect - findings
- normal pro-B, dec maturation, dec number of B cells, dec immunoglobulins of all classes
Selective IgA deficiency
- defect
- unknown, most common primary immunodeficiency - presentation
- majority asymptomatic
- can see sinopulmonary infections, GI infections, autoimmune dz, Anaphylaxis to IgA-containing blood products - findings
- IgA <7mg/dL with normal IgG, IgM, IgG vaccine titers
- False positive beta-HCG tests due to presence of heterophile antibody
Common variable immunodeficiency (CVID)
- defect
- defect in B cell maturation; many causes - presentation
- can be acquired in 20s-30s; inc risk of autoimmune dz, lymphoma, sinopulmonary infections - findings
- normal number of B cells; dec plasma cells, immunoglobulin
63
Q
Immune deficiencies:B cell disorders
- 3 types
- defect
- presentation
- findings
A
X-linked (Bruton’s) agammaglobulinemia
- defect
- X-linked recessive (inc in Boys). Defect in BTK, a tyrosine kinase gene–>no B cell maturation - presentation
- recurrent bacterial infections after 6 months (decrease maternal IgG) as a result of opsonization defect - findings
- normal pro-B, dec maturation, dec number of B cells, dec immunoglobulins of all classes
Selective IgA deficiency
- defect
- unknown, most common primary immunodeficiency - presentation
- majority asymptomatic
- can see sinopulmonary infections, GI infections, autoimmune dz, Anaphylaxis to IgA-containing blood products - findings
- IgA <7mg/dL with normal IgG, IgM, IgG vaccine titers
- False positive beta-HCG tests due to presence of heterophile antibody
Common variable immunodeficiency (CVID)
- defect
- defect in B cell maturation; many causes - presentation
- can be acquired in 20s-30s; inc risk of autoimmune dz, lymphoma, sinopulmonary infections - findings
- normal number of B cells; dec plasma cells, immunoglobulin
64
Q
immune deficiencies: phagocyte dysfunction
- 3 types
- defect
- presentation
- findings
A
Leukocyte adhesion deficiency (type 1)
- defect
- defect in LFA-1 integrin (CD18) protein on phagocytes - presentation
- recurrent bacterial infections, absent pus formation, delayed separation of umbilical cord - findings
- neutrophilia
Chediak-Higashi
- defect
- autosomal recessive; defect in lysosomal trafficking regulator gene (LYST)
- microtubule dysfunction in phagosome-lysosome fusion - presentation
- recurrent pyogenic infections by staphylococci and streptococci; partial albinism, peripheral neuropathy - findings
- giant granules in neutrophils
Chronic granulomatous disease
- defect
- lack of NADPH oxidase–> dec reactive oxygen species (eg. superoxide) and absent respiratory burst in neutrophils - presentation
- inc susceptibility to catalase-positive organisms (eg. S aureus, E.coli, Aspergillus) - findings
- abnormal dihydrorhodamine (DHR) flow cytometry test
- nitroblue tetrazolium dye reduction test no longer preferred
65
Q
immune deficiencies: B & T cell disorders:
- 4 types
- defect
- presentation
- findings
A
Severe combined immunodeficiency (SCID
- defect
- several types: defective IL-2 receptor (most common, X-linked), adenosine deasminase deficiency - presentation
- failure to thrive, chronic diarrhea, thrush,
- recurrent viral, bacterial, fungal, and protozoal infections
- absence of thymic shadow, germinal centers (lymph node biopsy), and B cells (peripheral blood smear)
- tx: bone marrow transplant (no allograft rejection) - findings
- dec T cell recombinant excision circles (TRECs)
- absence of thymic shadow, germinal centers (lymph node biopsy), and T cells (flow cytometry)
Ataxia-telangiectasia
2.defect
-defects in the ATM gene, which codes for DNA repair enzymes
3.presentation
-Triad: cerebellar defects (ataxia), spider angiomas (telangiectasis), IgA deficiency
4.findings
inc AFP
Hyper-IgM syndrome
- defect
- most commonly defective CD40L on helper T cells=inability to class switch - presentation
- severe pyogenic infections early in life - findings
- inc IgM, decrease maijorly IgA, dec IgM, thrombocytopenia
66
Q
immune deficiencies: phagocyte dysfunction
- 3 types
- defect
- presentation
- findings
A
Leukocyte adhesion deficiency (type 1)
- defect
- defect in LFA-1 integrin (CD18) protein on phagocytes - presentation
- recurrent bacterial infections, absent pus formation, delayed separation of umbilical cord - findings
- neutrophilia
Chediak-Higashi
- defect
- autosomal recessive; defect in lysosomal trafficking regulator gene (LYST)
- microtubule dysfunction in phagosome-lysosome fusion - presentation
- recurrent pyogenic infections by staphylococci and streptococci; partial albinism, peripheral neuropathy - findings
- giant granules in neutrophils
Chronic granulomatous disease
- defect
- lack of NADPH oxidase–> dec reactive oxygen species (eg. superoxide) and absent respiratory burst in neutrophils - presentation
- inc susceptibility to catalase-positive organisms (eg. S aureus, E.coli, Aspergillus) - findings
- abnormal dihydrorhodamine (DHR) flow cytometry test
- nitroblue tetrazolium dye reduction test no longer preferred
67
Q
Grafts
- autograft
- syngeneic graft
- allograft
- xenograft
A
- from self
- from identical twin or clone
- from nonidentical individual of same species
- from different species
68
Q
Transplant rejection:onset, pathogenesis, features
- hyperacute
- acute
A
hyperacute
- onset
- within minutes - pathogenesis,
- antibody mediated (type II) bcuz of presence of preformed anti-donor antibodies in the transplant recipient - features
- occludes graft vessels, causing ischemia and necrosis
acute
- onset
- weeks later - pathogenesis,
- cell mediated due to CTLs reacting against foreign MHCs
- reversible with immunosuppressants (eg. cyclosporine, muromonab-CD3 - features
- vasculitis of graft vessels with dense interstitial lymphocyte infiltrate
69
Q
Transplant rejection:onset, pathogenesis, features
- chronic
- graft vs. host
A
chronic
- onset,
- months to years - pathogenesis,
- class I-MHC nonself is perceived by CTLs as class I-MHC self presenting a nonself antigen - features
- irreversible: T ell and antibody-mediated vascular damage (obliterative vascular fibrosis); firbosis of graft tissue and blood vessels
graft vs. host
- onset,
- varies - pathogenesis,
- grafted immunocompetent T cells proliferate in the irradiated immunocompromised disease host and reject cells with foreign proteins resulting in severe organ dysfunction - features
- maculopapular rash, jaundice, hepatosplenomegaly, and diarrhea
- usually in bone marrow and liver transplant (organs rich in lymphocytes)
- potentially beneficial in bone marrow transplant
70
Q
Immunosuppressants: cyclosporine
- mechanism
- clinical use
- toxicity
A
- mechanism
- binds to cyclophilins
- complex blocks the differentiation and activation of T cells by inhibiting calcineurin, thus preventing the production of IL_2 and its receptor - clinical use
- suppresses organ rejection after transplantation; selected autoimmune disorders - toxicity
- nephrotoxicity, hypertension, hyperlipidemia, hyperglycemia, tremor, gingival hyperplasia
71
Q
Immunosuppressants: Tacrolimus (FK-506)
- mechanism
- clinical use
- toxicity
A
- mechanism
- similar to cyclosporine; binds to FK-binding protein, inhibiting calcineurin and secretion of IL-2 and other cytokines - clinical use
- potent immunosuppressive used in organ transplant recipients - toxicity
- similar to cyclosporine except no gingival hyperplasia and hirsutism
72
Q
Immunosuppressants: Sirolimus (rapamycin)
- mechanism
- clinical use
- toxicity
A
- mechanism
- inhibits mTOR, inhibts T cell proliferation in response to IL-2 - clinical use
- immunosuppression after kidney transplantation in combination with cyclosporine and corticosteroids
- also used with drug-eluting stents - toxicity
- hyperlipidemia, thrombocytopenia, leukopenia
73
Q
Immunosuppressants: azathioprine
- mechanism
- clinical use
- toxicity
A
- mechanism
- antimetabolite precursors of 6-nercaotiourine that interferes with the metabolism and synthesis of nucleic acids
- toxic to proliferating lymphocytes - clinical use
- kidney transplantation, autoimmune disorders (including glomerulonephritis and hemolytic anemia) - toxicity
- bone marrow suppression
- active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be increased by allopurinol
74
Q
therapeutic antibodies agent: target, clinical use
- Muromonab-CD3 (OKT3)
- Digoxin immune Fab
- Infliximab
- Adalimumab
- Abciximab
- Trastuzumab (Herceptin)
- Rituximab
- Omalizumab
A
- Muromonab-CD3 (OKT3)
- target–>CD3
- clinical use–>prevent acute transplant rejection - Digoxin immune Fab
- target–>Digoxin
- clinical use–>antidote for digoxin intoxication - Infliximab
- target–>TNF-alpha
- clinical use–>Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis - Adalimumab
- target–>TNF-alpha
- clinical use–>Crohn’s disease, rheumatoid arthritis, psoriatic arthritis - Abciximab
- target–>glycoprotein IIb/IIIa
- clinical use–>prevent cardiac ischemia in unstable angina and in patients treated with percutaneous coronary intervention - Trastuzumab (Herceptin)
- target–>HER2
- clinical use–>HER2-overexpressing breast cancer - Rituximab
- target–>CD20
- clinical use–>B cell non-Hodgkin’s lymphoma - Omalizumab
- target–>IgE
- clinical use–>additional line of treatment for severe asthma
75
Q
Recombinant cytokines agent & clinical uses:
- Aldesleukin (interleukin-2)
- Epoetin alfa (erythropoitin)
- Filgrastim (granulocyte colony-stimulating factor)
- Sargramostim (granulocyte-macrophage colony-stimulating factor)
- alpha-interferon
- beta-interferon
- gamma interferon
- Oprelvekin (interleukin-11)
- Thrombopoietin
A
- renal cell carcinoma, metastatic melanoma
- anemias (especially in renal failure)
- recovery of bone marrow
- revovery of bone marrow
- hepatitis B and C, Kaposi’s sarcoma, leukemia, malignant melanoma
- multiple sclerosis
- chronic granulomatous dz
- thrombocytopenia
- thrombocytopenia
76
Q
therapeutic antibodies agent: target, clinical use
1.
A
k
77
Q
Immune deficiencies: T cell disorder
- 4 types
- defect
- presentation
- findings
A
Thymic aplasia (DiGeorge syndrome)
- defect
- 22q11 deletion; failure to develop 3rd and 4th pharyngeal pouches - presentation
- tetany (hypocalcemia), recurrent viral/fungal infection (T-cell deficiency), congenital heart and great vessel defects - findings
- thymus and parathyroids fail to develop–> dec T cells, dec PTH, dec Ca2+.
- absent thymic shadow on CXR
IL-12 receptor deficiency
- defect
- dec Th2 response - presentation
- disseminated mycobacterial infections - findings
- dec IFN-gamma
Hyper-IgE syndrome (Job’s syndrome)
- defect
- Th1 cells fail to produce IFN-gamma–>inability of neutrophils to respond to chemotactic stimuli - presentation
- FATED: coarse Facies, cold (noninflamed) staphylococcal abscesses, retained primary Teeth, inc IgE, Dermatologic problems (eczema) - findings
- inc IgE
Chronic mucocutaneous candidiasis 2.defect -T cell dysfunction 3.presentation -Candida albicans infections of skin and mucous membranes 4.findings N/A
