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
Fc antibody region
- constant
- carboxy terminal
- complement binding at CH2 (IgG + IgM only)
- carbohydrate side chains
- determine isotype (IgM, IgD, etc)
26
antibody diversity is generated by:
- 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
immunoglobulin isotypes
- 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
IgG isotype
- 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
IgA
- 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
IgM
- 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
IgD
- unclear function
| - found on the surface of many B cells and in serum
32
IgE
- 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
antigen type & memory
1. thymus-independent antigen
2. thymus-dependent antigen
1. 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
2. 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
```
complement:
Overview
Activation
Functions
Opsonins
inhibitor
```
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
Complement disorders
1. C1 esterase inhibitor deficiency
2. C3 deficiency
3. C5-C9 deficiencies
4. DAF (GPI anchored enzyme) deficiency
1. hereditary angioedema. ACE inhibitors are contraindicated
2. severe, recurrent pyogenic sinus and respiratory tract infections; increase susceptibility to type III hypersensitivity rxns
3. recurrent Neisseria bacteremia
4. complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria (PNH)
36
Cytokines secredted by: macrophages
1. 5 types
2. description
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
Hot T-bone stEAk:
IL1-5 stimulates?
```
IL-1: fever (hot)
IL2-stimulates T cells
IL3-stimulates Bone marrow
IL4-stimulates IgE production
IL5-stimulates IgA production
```
38
Cytokines secreted by: all T cells
1. 2 types
2. description
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
Cytokines secreted by: Th1 cells
1. one type
2. description
Interferon-gamma
- activates macrophages and Th1 cells
- suppresses Th2 cells
- has antiviral and antitumor properties
40
Cytokines secreted by: Th2 cells
1. 3 types
2. description
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
interferon mechanism
- 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
cell surface proteins
1. T cells
2. Helper T cells
3. Cytotoxic cells
4. B cells
5. macropphages
6. NK cells
all cells except mature RBCs have MHC I
1. T cells
- TCR (binds antigen-MHC complex)
- CD3 (associated c TCR for signal transduction)
- CD28 (binds B7 on APC)
2. Helper T cells-->CD4, CD40 ligand
3. Cytotoxic cells-->CD8
4. 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
5. macropphages
- CD14, CD40
- MHC II, B7
- Fc & C3b receptors (enhanced phagocytosis)
6. NK cells
- CD16 (binds Fc of IgE), CD56 (unique marker for NK)
43
Anergy
- 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
Effects of bacterial toxins
- 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
antigen variation classic eg.
- 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
Passive immunity
1. means of acquisition
2. onset
3. duration
4. examples
5. notes
1. receiving preformed antibodies
2. rapid
3. short span of antibodies (half-life=3wks)
4. IgA in breast milk, antitoxin, humanized monoclonal antibody
5. after exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive)---To Be Healed Rapidly
47
Active immunity
1. means of acquisition
2. onset
3. duration
4. examples
5. notes
1. exposure to foreign antigens
2. slow
3. long lasting protection (memory)
4. natural infection, vaccines, toxoid
5. combined passive and active immunizations can be given in case of hepatitis B or rabies exposure
48
overview of vaccination
-vaccines are used to induce an active immune response (humoral and/or cellular) to specific pathogens
49
live attenuated vaccine
1. description
2. Pros/Cons
3. Examples
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
Inactivated or killed vaccine
1. description
2. Pros/Cons
3. Examples
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
Hypersensitivity Type: 1
- 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
Hypersensitivity Type: 2
- 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
Hypersensitivity Type: 3
1. serum sickness
2. arthus reaction
- 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
1. 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
Hypersensitivity Type: 4
-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
Hypersensitivity disorders: type I
1. Examples
2. presentation
1. anaphylaxis (bee sting, some food/drug allergies).
- allergic an datopic disorders (rhinitis, hay fever, eczema, hives, asthama)
2.immediate, anaphylactic, atopic
56
Hypersensitivity disorders: type II
1. Examples
2. presentation
1. 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
Hypersensitivity disorders: type III
1. Examples
2. presentation
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
Hypersensitivity disorders: type IV
1. Examples
2. presentation
1. 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
blood transfusion rnx: pathogens & presentation
1. allergic rnx
2. anaphylactic rnx
3. febrile nonhemolytic transfusion rnx (FNHTR)
4. Acute hemolytic transfusion rnx (HTR
1. allergic rnx
- type I hypersensitivity rnx against plasma proteins in transfused blood
- urticaria, pruritus, wheezing, fever, treat with antihistamines
2. anaphylactic rnx
- severe rnx; IgA-deficient individuals must receive blood produts that lack IgA
- dyspnea, bronchospasm, hypotension, respiratory arrrest, shock
3. febrile nonhemolytic transfusion rnx (FNHTR)
- type II hypersensitivity rnx. host antibodies against donor HLA antigens and leukocytes
- fever, HA, chills, flushing
4. 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
Autoantibodies & associated disorder
1. Antinuclear antibodies (ANA)
2. anti-dsDNA, anti-Smith
3. antihistone
4. rheumatoid factor, anti-CCP
5. anticentromere
6. anti-Scl-70 (anti-DNA topoisonmerase I)
7. antimitochondrial
8. IgA antiendomysial, IgA anti-tissue transglutaminase
9. anti-basement membrane
10. anti-desmoglein
11. antimicrosomal, antithyroglobulin
12. anti-Jo-1, anti-SRP, anti-Mi-2
13. anti-SSA (anti-Ro)
14. anti-U1 RNP (ribonucleoprotein)
15. anti-smooth muscle
16. anti-glutamate decarboxylase
17. c-ANCA (PR3-ANCA)
18. p-ANCA (MPO-ANCA)
19. anti-SSB (anti-La
1. SLE, nonspecific
2. SLE
3. drug-induced lupus
4. rheumatoid arthritis
5. scleroderma (CREST syndrome)
6. scleroderma (diffuse)
7. 1' billary cirrhosis
8. celiac disease
9. Goodpasteur's syndrome
10. Pemphigus vulgaris
11. Hashimoto's thyroiditis
12. Polymyositis, dermatomyositis
13. Sjogren's syndrome
14. mixed connective tissue disease
15. autoimmune hepatitis
16. type 1 DM
17. granulomatosis with polyangiitis (Wegener's)
18. microscropic polyangiitis, Churg-strauss syndrome
19. Sjogren's syndrome
61
Infections in immunodeficiency: bacteria, virus, fungi/parasites
1. Pathogen,
2. No T cells,
3. No B cells,
4. No granulocyte
5. No complement
Bacteria:
2. No T cells-->sepsis
3. No B cells-->encapsulated: Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitidis, Salmonella, Klebsiella pneumoniae, group B Strep (SHiN SKiS)
4. No granulocyte-->Staphylococcus, Burkholderia cepacia, Serratia, Nocardia
5. No complement-->Neiserria (no membrane attack complex)
Virus:
2. No T cells-->CMV, EBV, VZV, chronic infection with respiratory/GI viruses
3. No B cells-->enteroviral encephalitis, poliovirus (live vaccine contraindicated)
4. No granulocyte-->N/A
5. No complement-->N/A
Fungi/parasites
2. No T cells-->Candida, PCP
3. No B cells-->GI giardiasis (no IgA)
4. No granulocyte-->Candida, Aspergillus
5. No complement-->N/A
** B cell deficiencies tend to produce recurrent bacterial infections, whereas T cell deficiencies produce more fungal and viral infections
62
Immune deficiencies:B cell disorders
1. 3 types
2. defect
3. presentation
4. findings
X-linked (Bruton's) agammaglobulinemia
2. defect
- X-linked recessive (inc in Boys). Defect in BTK, a tyrosine kinase gene-->no B cell maturation
3. presentation
- recurrent bacterial infections after 6 months (decrease maternal IgG) as a result of opsonization defect
4. findings
- normal pro-B, dec maturation, dec number of B cells, dec immunoglobulins of all classes
Selective IgA deficiency
2. defect
- unknown, most common primary immunodeficiency
3. presentation
- majority asymptomatic
- can see sinopulmonary infections, GI infections, autoimmune dz, Anaphylaxis to IgA-containing blood products
4. 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)
2. defect
- defect in B cell maturation; many causes
3. presentation
- can be acquired in 20s-30s; inc risk of autoimmune dz, lymphoma, sinopulmonary infections
4. findings
- normal number of B cells; dec plasma cells, immunoglobulin
63
Immune deficiencies: T cell disorder
1. 4 types
2. defect
3. presentation
4. findings
Thymic aplasia (DiGeorge syndrome)
2. defect
- 22q11 deletion; failure to develop 3rd and 4th pharyngeal pouches
3. presentation
- tetany (hypocalcemia), recurrent viral/fungal infection (T-cell deficiency), congenital heart and great vessel defects
4. findings
- thymus and parathyroids fail to develop--> dec T cells, dec PTH, dec Ca2+.
- absent thymic shadow on CXR
IL-12 receptor deficiency
2. defect
- dec Th2 response
3. presentation
- disseminated mycobacterial infections
4. findings
- dec IFN-gamma
Hyper-IgE syndrome (Job's syndrome)
2. defect
- Th1 cells fail to produce IFN-gamma-->inability of neutrophils to respond to chemotactic stimuli
3. presentation
- FATED: coarse Facies, cold (noninflamed) staphylococcal abscesses, retained primary Teeth, inc IgE, Dermatologic problems (eczema)
4. 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
```
63
Immune deficiencies:B cell disorders
1. 3 types
2. defect
3. presentation
4. findings
X-linked (Bruton's) agammaglobulinemia
2. defect
- X-linked recessive (inc in Boys). Defect in BTK, a tyrosine kinase gene-->no B cell maturation
3. presentation
- recurrent bacterial infections after 6 months (decrease maternal IgG) as a result of opsonization defect
4. findings
- normal pro-B, dec maturation, dec number of B cells, dec immunoglobulins of all classes
Selective IgA deficiency
2. defect
- unknown, most common primary immunodeficiency
3. presentation
- majority asymptomatic
- can see sinopulmonary infections, GI infections, autoimmune dz, Anaphylaxis to IgA-containing blood products
4. 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)
2. defect
- defect in B cell maturation; many causes
3. presentation
- can be acquired in 20s-30s; inc risk of autoimmune dz, lymphoma, sinopulmonary infections
4. findings
- normal number of B cells; dec plasma cells, immunoglobulin
64
immune deficiencies: phagocyte dysfunction
1. 3 types
2. defect
3. presentation
4. findings
Leukocyte adhesion deficiency (type 1)
2. defect
- defect in LFA-1 integrin (CD18) protein on phagocytes
3. presentation
- recurrent bacterial infections, absent pus formation, delayed separation of umbilical cord
4. findings
- neutrophilia
Chediak-Higashi
2. defect
- autosomal recessive; defect in lysosomal trafficking regulator gene (LYST)
- microtubule dysfunction in phagosome-lysosome fusion
3. presentation
- recurrent pyogenic infections by staphylococci and streptococci; partial albinism, peripheral neuropathy
4. findings
- giant granules in neutrophils
Chronic granulomatous disease
2. defect
- lack of NADPH oxidase--> dec reactive oxygen species (eg. superoxide) and absent respiratory burst in neutrophils
3. presentation
- inc susceptibility to catalase-positive organisms (eg. S aureus, E.coli, Aspergillus)
4. findings
- abnormal dihydrorhodamine (DHR) flow cytometry test
- nitroblue tetrazolium dye reduction test no longer preferred
65
immune deficiencies: B & T cell disorders:
1. 4 types
2. defect
3. presentation
4. findings
Severe combined immunodeficiency (SCID
2. defect
- several types: defective IL-2 receptor (most common, X-linked), adenosine deasminase deficiency
3. 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)
4. 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
2. defect
- most commonly defective CD40L on helper T cells=inability to class switch
3. presentation
- severe pyogenic infections early in life
4. findings
- inc IgM, decrease maijorly IgA, dec IgM, thrombocytopenia
66
immune deficiencies: phagocyte dysfunction
1. 3 types
2. defect
3. presentation
4. findings
Leukocyte adhesion deficiency (type 1)
2. defect
- defect in LFA-1 integrin (CD18) protein on phagocytes
3. presentation
- recurrent bacterial infections, absent pus formation, delayed separation of umbilical cord
4. findings
- neutrophilia
Chediak-Higashi
2. defect
- autosomal recessive; defect in lysosomal trafficking regulator gene (LYST)
- microtubule dysfunction in phagosome-lysosome fusion
3. presentation
- recurrent pyogenic infections by staphylococci and streptococci; partial albinism, peripheral neuropathy
4. findings
- giant granules in neutrophils
Chronic granulomatous disease
2. defect
- lack of NADPH oxidase--> dec reactive oxygen species (eg. superoxide) and absent respiratory burst in neutrophils
3. presentation
- inc susceptibility to catalase-positive organisms (eg. S aureus, E.coli, Aspergillus)
4. findings
- abnormal dihydrorhodamine (DHR) flow cytometry test
- nitroblue tetrazolium dye reduction test no longer preferred
67
Grafts
1. autograft
2. syngeneic graft
3. allograft
4. xenograft
1. from self
2. from identical twin or clone
3. from nonidentical individual of same species
4. from different species
68
Transplant rejection:onset, pathogenesis, features
1. hyperacute
2. acute
hyperacute
1. onset
- within minutes
2. pathogenesis,
- antibody mediated (type II) bcuz of presence of preformed anti-donor antibodies in the transplant recipient
3. features
- occludes graft vessels, causing ischemia and necrosis
acute
1. onset
- weeks later
2. pathogenesis,
- cell mediated due to CTLs reacting against foreign MHCs
- reversible with immunosuppressants (eg. cyclosporine, muromonab-CD3
3. features
- vasculitis of graft vessels with dense interstitial lymphocyte infiltrate
69
Transplant rejection:onset, pathogenesis, features
1. chronic
2. graft vs. host
chronic
1. onset,
- months to years
2. pathogenesis,
- class I-MHC nonself is perceived by CTLs as class I-MHC self presenting a nonself antigen
3. features
- irreversible: T ell and antibody-mediated vascular damage (obliterative vascular fibrosis); firbosis of graft tissue and blood vessels
graft vs. host
1. onset,
- varies
2. pathogenesis,
- grafted immunocompetent T cells proliferate in the irradiated immunocompromised disease host and reject cells with foreign proteins resulting in severe organ dysfunction
3. 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
Immunosuppressants: cyclosporine
1. mechanism
2. clinical use
3. toxicity
1. 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
2. clinical use
- suppresses organ rejection after transplantation; selected autoimmune disorders
3. toxicity
- nephrotoxicity, hypertension, hyperlipidemia, hyperglycemia, tremor, gingival hyperplasia
71
Immunosuppressants: Tacrolimus (FK-506)
1. mechanism
2. clinical use
3. toxicity
1. mechanism
- similar to cyclosporine; binds to FK-binding protein, inhibiting calcineurin and secretion of IL-2 and other cytokines
2. clinical use
- potent immunosuppressive used in organ transplant recipients
3. toxicity
- similar to cyclosporine except no gingival hyperplasia and hirsutism
72
Immunosuppressants: Sirolimus (rapamycin)
1. mechanism
2. clinical use
3. toxicity
1. mechanism
- inhibits mTOR, inhibts T cell proliferation in response to IL-2
2. clinical use
- immunosuppression after kidney transplantation in combination with cyclosporine and corticosteroids
- also used with drug-eluting stents
3. toxicity
- hyperlipidemia, thrombocytopenia, leukopenia
73
Immunosuppressants: azathioprine
1. mechanism
2. clinical use
3. toxicity
1. mechanism
- antimetabolite precursors of 6-nercaotiourine that interferes with the metabolism and synthesis of nucleic acids
- toxic to proliferating lymphocytes
2. clinical use
- kidney transplantation, autoimmune disorders (including glomerulonephritis and hemolytic anemia)
3. toxicity
- bone marrow suppression
- active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be increased by allopurinol
74
therapeutic antibodies agent: target, clinical use
1. Muromonab-CD3 (OKT3)
2. Digoxin immune Fab
3. Infliximab
4. Adalimumab
5. Abciximab
6. Trastuzumab (Herceptin)
7. Rituximab
8. Omalizumab
1. Muromonab-CD3 (OKT3)
- target-->CD3
- clinical use-->prevent acute transplant rejection
2. Digoxin immune Fab
- target-->Digoxin
- clinical use-->antidote for digoxin intoxication
3. Infliximab
- target-->TNF-alpha
- clinical use-->Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis
4. Adalimumab
- target-->TNF-alpha
- clinical use-->Crohn's disease, rheumatoid arthritis, psoriatic arthritis
5. Abciximab
- target-->glycoprotein IIb/IIIa
- clinical use-->prevent cardiac ischemia in unstable angina and in patients treated with percutaneous coronary intervention
6. Trastuzumab (Herceptin)
- target-->HER2
- clinical use-->HER2-overexpressing breast cancer
7. Rituximab
- target-->CD20
- clinical use-->B cell non-Hodgkin's lymphoma
8. Omalizumab
- target-->IgE
- clinical use-->additional line of treatment for severe asthma
75
Recombinant cytokines agent & clinical uses:
1. Aldesleukin (interleukin-2)
2. Epoetin alfa (erythropoitin)
3. Filgrastim (granulocyte colony-stimulating factor)
4. Sargramostim (granulocyte-macrophage colony-stimulating factor)
5. alpha-interferon
6. beta-interferon
7. gamma interferon
8. Oprelvekin (interleukin-11)
9. Thrombopoietin
1. renal cell carcinoma, metastatic melanoma
2. anemias (especially in renal failure)
3. recovery of bone marrow
4. revovery of bone marrow
5. hepatitis B and C, Kaposi's sarcoma, leukemia, malignant melanoma
6. multiple sclerosis
7. chronic granulomatous dz
8. thrombocytopenia
9. thrombocytopenia
76
therapeutic antibodies agent: target, clinical use
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