Steve Irwin's Immunology Intellegence Flashcards
Lymph nodes are
secondary lymphoid organs that have many afferents, 1 or more efferents. Encapsulated, with trabeculae. Functions are nonspecific filtration by macrophages, storage of B and T cells, and immune response activation. Functions are nonspecific filtration by macrophages, storage of B and T cells and immune response activation.
Follicle of a lymph node
Site of B cell localization and proliferation. In outer cortex. primary follicles are dense and dormant. secondary follicles have pale central germinal centers and are active
Medulla of lymph node
Consists of medullary cords (closely pack lymphocytes and plasma cells) and medullary sinuses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages.
Paracortex of lymph node
Houses T cells. Region of cortex between follicles and medulla. Contains high endothelial venules through which T and B cells enter from blood. Not well developed in patients with DiGeorge syndrome.
Cervical Lymph nodes drain what area of the body
Head and Neck
Hilar Lymph nodes drain what area of the body
Lungs
Mediastinal Lymph nodes drain what area of the body
Trachea and esophagus
Axillary Lymph nodes drain what area of the body
Upper limb, breast, skin above umbilicus
Celiac Lymph nodes drain what area of the body
Liver stomach spleen pancreas and upper duodenum
Superior mesenteric Lymph nodes drain what area of the body
Lower duodenum, jejunum, ileum, colon to splenic flexure
Inferior Mesenteric Lymph nodes drain what area of the body
Lower rectum to anal canal above the pectinate line, bladder, vagina (middle third), prostate
Para-aortic Lymph nodes drain what area of the body
Tests, ovaries, kidneys, uterus
Superficial inguinal Lymph nodes drain what area of the body
Anal canal (below pectinate line), skin below umbilicus (except popliteal territory)
Popliteal Lymph nodes drain what area of the body
Dorsolateral foot posterior calf
Right lymphatic duct drains what are
drains right side of body above diaphragm
Sinusoids of spleen
long, vascular channels in red pulp with fenestrated barrel hoop basement membrane. Macrophages found nearby
Where are T and B cells found in spleen
T cells: found in periarterial lymphatic sheath within the white pulp
B cells: found in follicles within the white pulp of the spleen.
What happens in the marginal zone of spleen
In between the red and white pulp: contains APCs and specialized B cells, where APCs present blood-borne antigens
Macrophages in the spleen do what?
Remove encapsulated spleen
Splenic dysfunction will lead to what
Decreased IgM leading to decreased complement causing decreased C3b opsonization and increased susceptibility to encapsulated organisms
Leads to infections form SHiNE SKiS:
Strep pneumoniae, H Influenza, Neisseria meningitidis, E coli, Salmonella, Klebsiella pneumoniae, group b Strep.
Thymus function:
Site of T cell differentiation and maturation. Encapsulated. from epithelium of 3rd pharyngeal pouch. Lymphocytes of mesenchymal origin. Cortex is dense with immature T cells; medulla is pale with mature T cells and Hassal corpuscles containing epithelial reticular cells.
Components of innate immunity
Neutrophils, macrophages, monocytes, dendritic cells, NK cells (lymphoid origin), complement
Components of adaptive immunity
T cells, B cells, circulating antibodies
What are the secreted proteins of innate immunity
lysozyme, complement, CRP, defensins
How does innate immune system recognize pathogen
Toll like receptors: pathogen recognition receptors that recognize pathogen-associated molecular patterns (PAMPs). Examples of PAMPs are LPS, flagellin, ssRNA
Gene loci of MHC I
HLA-A, HLA-B, HLA-C
Gene loci of MHC II
HLA-DR, HLA-DP, HLA-DQ
MHC I: binds
TCR and CD8
MHC II: binds
TCR and CD4
Function of MHC I
Present endogenously synthesized antigens (e.g. viral) to CD8+ cytotoxic T cells
Function of MHC II
Present exogenously synthesized proteins (e.g. bacterial proteins, viral capsid proteins) to T-Helper Cells
How is antigen loaded in MHC I
antigen peptides loaded onto MHC I in RER after delivery via TAP peptide transporter
How is antigen loaded in MHC II
Antigen loaded following release of invariant chain in an acidified endosome
HLA subtypes associated with: Hemochromatosis
A3
Diseases associated with B27 HLA
Psoriatic arthritis, Ankylosing spondylitis, arthritis of Inflammatory bowel disease, Reactive arthritis (PAIR)
This group of disorders is called seronegative arthropathies
HLA subtypes associated with: Celiac disease
DQ2/DQ8
Diseases associated with HLA DR2
Multiple sclerosis, hay fever, SLE, Goodpasture syndrome
Diseases associated with HLA DR3
Daibetes mellitus type 1, SLE, Graves disease
Diseases associated with HLA DR4
Rheumatoid arthritis, diabetes mellitus type 1
“there are 4 walls in a rheum”
Diseases associated with HLA DR5
pernicious anemia causing vitamin B12 deficiency, Hashimoto thyroiditis
Natural killer cells
Uses perforin and granzymes to induce apoptosis of virally infected cells and tumor cells. Only lymphocyte member of innate immune system.
Actively enhanced by IL-2, IL-12, IFN-beta, and IFN-alpha
induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of MHC 1 on target cell surface.
Also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating the NK cell).
Major functions of B cells
Recognize antigen-undergo somatic hypermutation to optimize antigen specificity. Produce antibody-differentiate into plasma cells to secrete specific immunoglobulins.
Maintain immunologic memory-memory b cells persist and accelerate future response to antigen
major functions of T cells
CD4+: 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 rejection
Rule of 8 “MHC 2 x CD4=8 and MHC 1 x 8=8”
Differentiation of T cells: Positive selection
happens in thymic cortex, T cells expressing TCRs capable of binding surface self MHC molecules survive
Differentiation of T cells: negative selection
Medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis
How to get to a Th1 cell from a helper T cell
IL-12
how to get to a Th2 cell from a helper T cell
IL-4
How to get to a TH17 cell from a helper T cell
TGF-beta + IL-6
How to get to a Treg cell from a helper T cell
TGF-beta
Naive T cell activation
- foreign antigen 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) cell.
- Costimulatory signal is given by interaction of B7 (on dendritic) and CD28 (on T cell)
- Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virus infected cell
B cell activation and class switching
- helper T cell activation is completed
- B cell receptor-mediated endocytosis; foreign antigen is presented on MHC II and recognized by TCR on Th cell.
- CD40 receptor on B cell binds CD40 ligand on Th cell
- Th cell secretes cytokines that determine Ig class switching of B cell. B cell activates and undergoes class switching, affinity maturation, and antibody production
Th1 helper T cell: activated by? Activates? Inhibited by?
Secretes IFN-gamma
Activates macrophages and cytotoxic T lymphocytes (CD8)
Inhibited by IL-4 and IL-10 (from Th2 cells)
Th2 cells: activated by? Activates? inhibited by?
secretes IL-4, IL-5, IL-6, IL-13
Recruits eosinophils for parasite defense and promotes IgE production by B cells
Inhibited by IFN-gamma (from Th1 cells)
Macrophage-Lymphocyte interaction
Macrophages release IL-12, which stimulates T cells to differentiate into Th1 cells, Th1 cells release IFN-gamma to stimulate macrophages.
Cytotoxic T cells
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 B- a serine protease, activates apoptosis inside target cells; granulysin-antimicrobial, induces apoptosis).
Cytotoxic T cells have CD8, which binds to MHC I on virus-infected cells
Regulatory T cells
Help maintain specific immune tolerance by suppressing CD4 and CD8 T cell effector function. Identified by expression of cell surface markers CD3, CD4, CD25 (alpha chain of IL-2 receptor), and transcription factor FOXP3
Activated regulatory T cells produce anti-inflammatory cytokines like IL-10 and TGF-beta
Fab region of antibody
Antigent-binding fragment
Determine idiotype: unique antigen binding pocket; only 1 antigenic specificity expressed per B cell
Fc region of antibody
Constant, Carboxy terminal, Complement binding, Carbohydrate side chains, Determines isotype (IgM, IgD….)`
Antibody diversity is generated by
Random Recombination of VJ (light chain) or V(D)J (heavy chain) genes
random combinations of heavy chains with light chains
Somatic hypermutation following antigen stimulation
Addition of nucleotides to DNA during recombination by terminal deoxynucelotidyl transferase
what part of antibody recognizes antigen
Variable part of the L and H chains
Fc portion of IgM and IgG fixes what
fixes complement
What do the heavy and light chains contribute to in the structure of an antibody
Heavy: both Fc and Fab fractions
Light: only Fab fraction
What do mature B lymphocytes express on their surface
IgM and IgD
(may differentiate in germinal centers of lymph nodes by isotype switching into plasma cells that secrete IgA, IgE, or IgG
IgG
main antibody in secondary (delayed) response to antigen. Most abundant isotype in serum. Fixes complement, crosses the placenta (provides infants with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses.
IgA
Prevents attachment of bacteria and viruses to mucous membranes; does not fix compliment
Monomer (in circulation) or Dimer (when secreted).
Crosses epithelial cells by transcytosis. Most produced antibody overall, but released into secretions (tears, saliva, mucus) and early breast milk (colostrum). Picks up secretory component from epithelial cells before secretions
IgM
Produces in the primary (immediate) response to antigen Fixes complement, does not cross placenta, Antigen receptor on the surface of B cells. Monomer on B cell or pentamer when secreted. Shape of pentamer allows it to efficiently trap free antigens out of tissue while humoral response evolves. #1 antibody if no class switching.
IgD
Unclear formation. found on the surface of many B cells and in serum
IgE
Bind mast cells and basophils; cross-links when exposed to allergen, mediating immediate (type-1) hypersensitivity through release of inflammatory mediators such as histamine. Mediates immunity to worms by activating eosinophils. Lowers concentration in serum.
Antigen type and memory: Thymus-independent antigens
Antigens lacking a peptide component (e.g. lipopolysaccharides form gram - bacteria); cannot be presented by MHC to T cells. Weakly or nonimmunogenic; vaccines often require boosters (e.g. pneumococcal polysaccharide vaccine). So major antibody will be IgM since no class switching
Antigen type and memory: thymus dependent antigens
Antigens containing a protein component (e.g. diptheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40 ligand reaction).
What are acute phase reactants
Factors whose serum concentrations change significantly in response to inflammation; produced by the liver in both acute and chronic inflammatory states. Induced by IL-1, 6, TNF alpha, and IFN-gamma
Acute Phase reactant: Serum amyloid A
Upregulated: prolonged elevation can lead to amyloidosis
Acute Phase reactant: C reactive protein
Upregulated: opsonin that fixes complement and facilitates phagocytosis
Acute Phase reactant: Ferritin
Upregulated: Binds and sequesters iron to inhibit microbial scavenging
Acute Phase reactant: Fibrinogen
Upregulated: Coagulation factor; promotes endothelial repair; correlates with ESR
Acute Phase reactant: Hepcidin
upregulated: Prevents release of iron bound by ferritin can lead to anemia of chronic disease
Acute Phase reactant: albumin
downregulated: reduction conserves amino acids for positive reactants
Acute Phase reactant: Transferrin
Downregulated: internalized by macrophages to sequester iron
Membrane Attack Complex (MAC) defends against what type of bacteria
Gram negative bacteria
Name the three complement pathways
Classic, Alternative and Lectin
How do you activate the different complement pathways
Classic: IgG or IgM mediated
Alternative pathway: microbe surface molecules
Lectin pathway: mannose or other sugars on microbe surface
What does this complement component do: C3b
opsonization, helps clear immune complexes
What does this complement component do: C3a
anaphylaxis
What does this complement component do: C4a
anaphylaxis
What does this complement component do: C5a
anaphylaxis and neutrophil chemotaxis
What does this complement component do: C5b-9
cytolysis by membrane attack complex
How do you inhibit complement system
Decay-accelerating factor (DAF, aka CD55) and C1 esterase inhibitor help prevent complement activation on self cells (e.g. RBC)
What is the C3 convertase for the alternative pathway
C3bBb
What is the C3 convertase for the lectin pathway
C4b2b
What is the C3 convertase for the classic pathway
C4b2b
What is the C5 convertase for the alternative pathway
C3bBb3b
What is the C5 convertase for the lectin pathway
C4b2b3b
What is the C5 convertase for the Classic pathway
C4b2b3b
C1 esterase inhibitor deficiency
Causes hereditary angioedema. ACE inhibitors are contraindicated
C3 deficiency
Increases risk for severe, recurrent pyogenic sinus and respiratory infections; increase susceptibility to type III hypersensitivity reactions
C5-C9 deficiency
Increase susceptibility to recurrent Neisseria bacteremia
DAF (GPI anchored enzyme) deficiency
Causes complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria
IL-1
secreted from macrophages
An endogenous pyrogen also called osteoclast-activating factor
Causes fever, acute inflammation. Activates endothelium to express adhesion molecules; induces endothelium to express adhesion molecules; induces chemokine secretion to recruit leukocytes.
IL-6
secreted by macrophages and Th2 cells
an endogenous pyrogen
causes fever and stimulates production of acute-phase proteins
IL-8
Secreted by macrophages
Major chemotactic factor for neutrophils.
IL-12
secreted by macrophages
induces differentiation of T cells into Th1 cells. Activates NK cells. Also secreted by B cells
TNF-alpha
secreted by macrophages
Mediates septic shock. Activates endothelium. Causes leukocyte recruitment, vascular leak
IL-2
Secreted by all T cells
Stimulates Growth of helper, cytotoxic and regulatory T cells
IL-3
Secreted by all T cells
Supports the growth and differentiation of bone marrow stem cells. Functions like GM-CSF
Interferon-gamma
Secreted from Th1 cells
Has antiviral and anti-tumor properties. Activates NK cells to kill virus-infected cells, Increases MHC expression and antigen presentation in all cells
IL-4
Secreted from Th2 cells Induces differentiation into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG
IL-5
Secreted from Th2 cells Promotes differentiation of B cells. Enhances class switching to IgA. Stimulates the Growth and differentiation of eosinophils.
IL-10
Secreted form Th2 cells and regulatory T cells
Modulates inflammation response. Inhibits actions of activated T cells and Th1.
TGF-Beta has similar actions to IL-10 because it it involved in inhibiting inflammation
Cytokines secreted by macrophages
IL-1, IL-6, IL-8, IL-12, INF alpha
Cytokines secreted by all T cells
IL-2, IL-3
Cytokines secreted by Th1 cells
IL-2, IL-3 (all t cells)
Interferon-gamma
Cytokines secreted by Th2 cells
IL-2, IL-3 (all t cells)
IL-4, IL-5, IL-10
Interferon alpha and Beta
Interferes with viruses
A part of innate host defense against both RNA and DNA viruses. Interferons are glycoproteins synthesized by viral-infected cells that act locally on uninfected cells, “priming” them for viral defense. When a virus infects “primed” cells, viral dsRNA activates: RNAase L (degrades viral/host mRNA) and Protein kinase (inhibition of viral/host protein synthesis)
Essentially results in apoptosis, thereby interrupting viral amplifications
Cell surface protein: T cells
TCR (binds antigen-MHC complex)
CD3 (associated with TCR for signal transduction)
CD28 (binds B7 on APC)
Cell surface protein: Helper T cells
CD4 and CD40 ligand
Cell surface protein: cytotoxic T cells
CD8
Cell surface protein: B cells
Ig (binds antigen)
CD-19, CD 20, CD21 (receptor for EBV), CD40
MHC II, B7
(has CD5 when premature, if mature and has CD5 then they have Chronic lymphocytic leukemia)
Cell surface proteins on Macrophages
CD14, CD40
MHC II, B7
Fc and C3b receptors (enhanced phagocytosis)
Cell surface proteins on NK cells
CD16 (binds Fc of IgG), CD56 (unique marker for NK)
Anergy
Self-reactive T cells become nonreactive without co-stimulatory molecule. B cells also become anergic, but tolerance is less complete than in T cells
Effects of bacterial toxins: Superantigens (pyogenes and aureus)-
cross-link 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.
Effects of bacterial toxins: endotoxins/lipopolysaccharide (gram negative bacteria):
stimulate macrophages by binding to endotoxin receptor CD14; Th cells are not involved
Passive immunity
Receive preformed antibodies
Rapid Onset
Short span of antibodies (3 week half life)
Examples: IgA in breast milk, maternal IgG crossing placenta, antitoxin (Tetanus, botulinum, HBV, Rabies), humanized monoclonal antibody
Active immunity
Exposure to foreign antigens gives you the immunity
Slow onset
Long-lasting protection
Examples would be natural infection, vaccines, toxoid
Combine active and passive immunizations are given after exposure to what diseases
Hepatitis B and Rabies
Vaccinations cause:
Autism
Source: jennymaccarthy_antivax_naturopathy@blogspot.com
Live attenuated viruses
Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Mainly induces a cellular response.
Induces strong often lifelong immunity
May revert to virulent form and often contraindicated in pregnancy and immune deficiency
Examples: MMR, Sabin polio, intranasal influenza, varicella, yellow fever
Inactivated virus or killed virus vaccines
Pathogen in inactivated by heat or chemicals; maintaining epitope structure on surface antigens is important for immune response. Humoral immunity induced.
Stable and safer than live vaccines
Weaker immunity response; booster shots usually required
Examples: Cholera, Hepatitis A, Polio (salk), influenza injection form, rabies
Type 1 hypersensitivity
Anaphylactic and atopic- free antigen cross links IgE on presensitized mast cells and basophils, triggering immediate release of vasoactive amines that act at postcapillary venules (i.e. histamine). Reaction develops rapidly after antigen exposure because of preformed antibody. Delayed response follows due to production of arachidonic acid metabolites (e.g. leukotrienes) Get urticaria (hives) Tests: skin test for specific IgE
Type 2 Hypersensitivity
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, usually due to NK cells or macrophages.
Type II is cy-2-toxic
Antibody + complement leads to MAC
Test: direct and indirect Coombs’
Direct Coombs’
Detect antibodies that have adhered to patient’s RBCs (e.g. test an RH + infant of an Rh - mother)
Indirect Coombs’
Detects antibodies that can adhere to other RBCs (e.g. test an Rh- woman for Rh+ antibodies)
Type III hypersensitivity
Immune complex- antigen antibody (IgG) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes
Type 3=3 things get stuck together= antigen-antibody-complement
Serum sickness
An immune complex disease (type 3) in which antibodies to foreign proteins are produced (takes 5 days). Immune complexes form and are deposited in membranes, where the fix complement (leads to tissue damage). More common that Arthus reaction
Most serum sicknesses are now caused by drugs (not serum) acting as haptens. Fever, urticaria, arthralgias, proteinuria, lymphadenopathy 5-10 days after antigen exposure.
Arthus reaction
a local subacute antibody mediated hypersensitivity (type 3) reaction. Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin. Characterized by edema, necrosis, and activation of complement
Antigen-antibody complexes cause the Arthus reaction
Test: immunofluorescent staining
(e.g. tetanus booster causing swelling in arm, you already have pre formed antibodies which react with antigen)
Type IV hypersensitivity
Delayed (t cell mediated) type- sensitized T lymphocytes encounter antigen and then release lymphokines (leads to macrophage activation; no antibody involved)
Cell mediated=not transferable by serum
4T’s= T lymphocytes, Transplant rejections, Tb skin test, Touching (contact dermatitis).
Blood transfusion reactions: allergic reaction
Type 1 hypersensitivity reaction against plasma proteins in transfused blood.
Get Urticaria, pruritus, wheezing, fever.
Treat with antihistamines
Blood transfusion reactions: anaphylactic reaction
severe allergic reaction. IgA-deficient individuals must receive blood products that lack IgA
Get dyspnea, bronchospasm, hypotension, respiratory arrest, shock.
Blood transfusion reactions: Febrile nonhemolytic transfusion reaction
Type II hypersensitivity reaction. Host antibodies against HLA antigens and leukocytes
Get Fever, Headaches, chills, flushing
Blood transfusion reactions: Acute Hemolytic transfusion reaction
Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs).
Get fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinemia (intravascular), jaundice (extravascular hemolysis)
What disease is associated with this auto-antibody: Anti-ACh
Myasthenia gravis
What disease is associated with this auto-antibody: anti-basement membrane
Goodpasture Syndrome
What disease is associated with this auto-antibody: anti-cardiopilin
SLE
What disease is associated with this auto-antibody: anticentromere
Limited scleroderma (CREST)
What disease is associated with this auto-antibody: anti-desmoglein
Pemphigus vulgaris
What disease is associated with this auto-antibody: anti-dsDNA, anti-Smith
SLE
What disease is associated with this auto-antibody: Anti-glutamate decarboxylase
Type 1 diabetes
What disease is associated with this auto-antibody: anti-hemidesmosome
bullous pemphigoid
What disease is associated with this auto-antibody: Antihistone
Drug-induced lupus
What disease is associated with this auto-antibody: anti-Jo-1, anti SRP, Anti-mi-2
Polymyositis, Dermatomyositis
What disease is associated with this auto-antibody: Antimicrosomal, antithyroglobulin
Hoshimoto thyroiditis
What disease is associated with this auto-antibody: Antimitochondrial
Primary Biliary cirrhosis
What disease is associated with this auto-antibody: antinuclear antibodies
SLE, nonspecific
What disease is associated with this auto-antibody: Anti-Scl-70 (anti-DNA topoisomerase I)
Scleroderma (diffuse)
What disease is associated with this auto-antibody: anti-smooth muscle
Autoimmune hepatitis
What disease is associated with this auto-antibody: Anti-SSA, anti-SSB (anti-Ro, anti-La)
Sjorgen syndrome
What disease is associated with this auto-antibody: Anti-TSH
Graves disease
What disease is associated with this auto-antibody: Anti-U1 RNP (ribonucleoprotein)
Mixed connective tissue
What disease is associated with this auto-antibody: c-ANCA (PR3-ANCA)
Granulomatosis with polyangiitis (Wegener)
What disease is associated with this auto-antibody: IgA anti-endomysial, IgA anti-tissue transglutaminase
Celiac disease
What disease is associated with this auto-antibody: p-ANCA (MPO-ANCA)
Microscopic polyangitis, Churg-Strauss Syndrome
What disease is associated with this auto-antibody: Rheumatoid factor (antibody, most commonly IgM, specific to IgG Fc region), anti-CCP
Rheumatoid arthritis
What bacteria are bad if you have no B cells
Fine unless you get SHiNE SKiS
Strep pneumoniae, H influenza type b, Neisseria meningitidis, E coli, Salmonella, Klebsiella pneumoniae, group b Strep
What bacteria are bad if you have no granulocytes
fine unless you get, staphylococcus, Burkholderia cepacia, Serratia, Nocardia
Then you cannot fight it off
What bacteria are bad if you have no complement
Be fine, unless you get Neisseria (no MAC)
If you have no T cells what viral infection should you stay away from
CMV, EBV, JCV, VZV, Chronic infection with respiratory/GI viruses
If you have no B cells, what Viruses are really bad
Enteroviral encephalitis, poliovirus
And do not give live vaccine
If you have no T cells, what fungi are really bad
Candida, PCP (not the drug! Pneumocystis pneumonia)
If you have no granulocytes, what fungi are really bad
Candida, Aspergillus
Immunodeficiencies: Compare T cell VS B cell deficiency
T cell deficiency: tend to produce more recurrent fungal and viral infections
B cell deficiency: tend to produce more recurrent bacterial infections
X-linked (Bruton) agammaglobulinemia
Defect in BTK, a tyrosine kinase gene leading to no B cell maturation. X-linked recessive
Presents: recurrent bacterial and enteroviral infections after 6 months (lose maternal IgG)
Findings: normal CD19+ B cell count, decrease pro-B, decrease Ig of all classes. Absent/scanty lymph nodes and tonsils
Selective IgA deficiency
unknown. most common primary immunodeficiency. decreased IgA=> increase class switching to IgE=> more atopy (allergies)
Presentation: Majority asymptomatic, can see airway and GI infections, Autoimmune disease, Atopy, Anaphylaxis to IgA containing products.
Findings: decreased plasma cells, decreased immunoglobulins
Common variable immunodeficiency
Defect in B cell differentiation. Many causes
Presentation: can be acquired in 20s and 30s; increased risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections.
Findings: decrease plasma cells, decrease immunoglobulins, can still have intact cellular immunity (e.g. will respond to candida skin test)
Thymic aplasia (Digeorge syndrome)
22q11 deletion; failure of 3rd and 4th pharyngeal pouches to develop leading to absent thymus and parathyroids.
Presentation: Tetany (hypocalcemia), recurrent viral/fungal infections (T-cell deficiency), conotruncal abnormalities (e.g. tetrology of Fallot, Truncus arteriosus).
Findings: decreased T cells, decreased PTH, decreased Calcium. Abscent thymic shadow on CXR, 22q11 deletion seen on FISH
IL-12 receptor deficiency
Decreased Th1 response. Autosomal recessive
Presentation: Disseminated mycobacterial and fungal infections; may present after administration of BCG (TB) vaccine.
Findings: decreased IFN-gamma
Autosomal dominant hyper-IgE syndrome (Job Syndrome)
Deficiency of Th17 cells due to STAT3 mutation leading to impaired recruitment of neutrophils to sites of infection
Presentation: FATED; coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary Teeth, increased igE, Dermatologic problems (eczema)
Findings: Increased IgE and decreased IFN-gamma
Chronic Mucocutaneous candidiasis
T-cell dysfunction. Many causes
Presentation: Noninvasive Candida albicans infections of skin and mucous membranes.
Findings: Absent in vitro T-cell proliferation in response to Candida antigens. Absent cutaneous reaction to Candida antigens.
Severe combined immunodeficiency (SCID)
Several types including defective IL-2R gamma chain (most common, X linked), adenosine deaminase deficiency (autosomal recessive).
Presentation: failure to thrive, chronic diarrhea, thrush. Recurrent viral, bacterial, fungal, and protozoal infections.
Treatment: bone marrow transplant (no concern for rejection)
Findings: T cell receptor excision circles (TRECs); Absence of thymic shadow (CXR), germinal centers (lymph node biopsy), and T cells (flow cytometry)
Ataxia-telangiectasia
Defects in ATM gene leading to DNA double stranded breaks causing cell cycle arrest
Presentation: cerebellar defects (ataxia), spider angiomas (telangiectasia of eyes and skin), IgA deficiency, increased change of Hodgkins and lymphomas
Findings: Increased AFP; decreased IgA, IgG and IgE; lymphopenia, cerebellar atrophy;
autosomal recessive
Hyper-IgM syndrome
Most commonly due to defective CD40L on Th cells=class switching defect; X linked recessive
Presentation: Severe pyogenic infections early in life; opportunistic infection with Pneumocystis, Cryptosporidium, CMV
Findings: Increased IgM; Greatly decreased IgG, IgA, IgE
Wiskott-Aldrich syndrome
Mutation in WAS gene (x-linked recessive); T cells unable to reorganize actin cytoskeleton.
Presentation (WATER): Wiskott-Aldrich, Thrombocytopenic purpura, Eczema, Recurrent infections; increased risk of autoimmune diseases and non hodgkin lymphoma
Leukocyte adhesion deficiency Type 1
Defect in LFA-1 integrin (CD18) protein on phagocytes; impaired migration and chemotaxis; autosomal recessive.
Recurrent bacterial skin and mucosal infections, absent pus formation, impaired wound healing, delayed separation of umbilical cord (>30 days).
Findings: increased neutrophils, absence of neutrophils at infection sites
Chediak-Higashi syndrome
Defect in lysosomal trafficking regulator gene (LYST); microtubule dysfunction in phagosome-lysosome fusion; autosomal recessive
Presentation: Recurrent pyogenic infections by staph and strep, partial albinism, peripheral neuropathy, progressive neurodegeneration, infiltrative lymphohistiocytosis.
Findings: increased neutrophils, absence of neutrophils at infection site
Chronic granulomatous disease
Defect of NADPH oxidase leading to a decrease in reactive oxygen species (e.g. superoxide) and absent respiratory burst in neutrophils; X linked recessive
Presentation: increased susceptibility to catalase positive organisms (PLACESS): Pseudomonas, Listeria, Aspergillus, Candidia, E coli, S. aureus, Serratia
Findings: abnormal dihydrorhodamine (flow cytometry) test. Nitroblue tetrazolium dye reduction test is negative (test out of favor now)
What is an autograft
graft from self to self
What is a syngeneic graft
from identical twin or clone (because clones are thing…..)
what is an Allograft
From nonidentical individual of same species
what is a Xenograft
a graft from a different species
Transplant rejection: Hyperacute
occurs within minutes
Pathogenesis: pre-existing antibodies react to donor antigen (type II reaction), activate complement.
Features: widespread thrombosis of graft vessels leading to ischemia/necrosis. Graft must be removed.
Transplant rejection: Acute
occurs in weeks to months
Pathogenesis: Cellular: CTLs activated against donor MHCs. Humoral: similiar to hyperacute but antibodies develop after transplant
Features: Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate. Prevent/reverse with immunosuppressants
Transplant rejection: Chronic
occurs in Months to years
Pathogenesis: Recipient T cells perceive donor MHC as recipient MHC and react against donor antigens present. Both cellular and humoral components
Features: irreversible, T cell and antibody mediated damage. Organ specific: Heart-atherosclerosis, Lungs-bronchiolitis obliterans, Liver-Vanishing bile ducts, Kidney-vascular fibrosis and glomerulopathy
Transplant rejection: Graft-Versus-host disease
Onset varies
Pathogenesis: grafted immunocompetent T cells proliferate in the immunocompromised host and reject host cells with “foreign” proteins leading to severe organ dysfunction.
Features: Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly, Usually in bone marrow and liver transplants (high in lymphocytes). Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor effect)
Cyclosporine
Mechanism: calcineurin inhibitor; binds cyclophilin; blocks t cell activation by preventing IL-2 transcription
Uses: transplant rejection prophylaxis, psoriasis, rheumatoid arthritis
Toxicity: !Nephrotoxicity!: hypertension, hyperlipidemia, hyperglycemia, tremor, hirsutism, gingival hyperplasia (all of the hypers)
Tacrolimus
Calcineurin inhibitor; binds FK506 binding protein (FKBP) (all -limus drugs bind FKBP). Blocks T cell activation by preventing IL-2 transcription.
Uses. Transplant rejection prophylaxis
Toxicity: similar to cyclosporine (nephrotoxic), increase risk of diabetes and neurotoxicity; no gingival hyperplasia or hirsutism.
Sirolimus (Rapamycin)
mTOR inhibitor; binds FKBP. Blocks T cell activation and B cell differentiation by preventing IL-2 transduction.
Uses: Kidney transplant rejection prophylaxis
Toxicity: anemia, thrombocytopenia, leukopenia, insulin resistance, hyperlipidemia; non-nephrotoxic.
Notes: Kidney “sir-vives.” Synergistic with cyclosporine. Also used in drug eluting stents.
Basiliximab
Monoclonal antibody; blocks IL-2R
Uses: kidney transplant rejection prophylaxis.
Toxicity: edema, hypertension, Tremor
Azathioprine
antimetabolite precursor for 6-mercaptopurine; inhibits lymphocyte proliferation by blocking nucleotide synthesis.
Uses: Transplant rejection prophylaxis, rheumatoid arthritis, Crohn disease, Glomerulonephritis, other autoimmune conditions
Toxicity: Leukopenia, anemia, thrombocytopenia
Note: 6-MP is degraded by xanthine oxidase so toxicity is increased by allopurinol
Glucocorticoids
Inhibit NF-kappaB. Suppress both B and T cell function by decreasing transcription of many cytokines.
Uses: transplant rejection prophylaxis (immune suppression), many autoimmune disorders, inflammation.
Toxicity: hyperglycemia, osteoporosis, central obesity, muscle breakdown, psychosis, acne, hypertension, cataracts, peptic ulcers.
Can cause iatrogenic Cushing syndrome
Recombinant cytokines and their clinical uses: Epoetin alfa
erythropoietin Treats anemias (Especially in renal failure)
Recombinant cytokines and their clinical uses: Thrombopoietin
Treats thrombocytopenia
Recombinant cytokines and their clinical uses: Oprelvekin
(IL-11) Treats thrombocytopenia
Recombinant cytokines and their clinical uses: Filgrastim
granulocyte colony-stimulating factor
Used for recovery of bone marrow
Recombinant cytokines and their clinical uses: Sargramostim
Granulocyte-macrophage colony-stimulating factor)
used for the recovery of bone marrow
Recombinant cytokines and their clinical uses: Aldesleukin
IL-2
Used for Renal cell carcinoma, metastatic melanoma
Recombinant cytokines and their clinical uses: IFN-alpha
used for Chronic hep B and C, Kaposi sarcoma, Hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma
Recombinant cytokines and their clinical uses: IFN-beta
Used for multiple sclerosis
Recombinant cytokines and their clinical uses: IFN-gamma
Used for chronic granulomatous disease
Target and use for: alemtuzumab
targets CD52
used for CLL
aLYMtuzumab for chronic LYMphocytic leukemia
Target and use for: Bevacizumab
target is VEGF
used for: colorectal cancer, renal cell carcinoma
Target and use for: Cetuximab
target is EGFR
used for Stage IV colorectal cancer, head and neck cancer
Target and use for: Rituximab
target is CD20
Clinical use is B cell non hodgkin lymphoma, rheumatoid arthritis (with MTX), ITP
Target and use for: Trastuzumab
Target is HER2/neu
Used for breast cancer, gastric cancer
“HER2-tras2zumab
Target and use for: Inflizimab, adaliumab
Target is TNF-alpha
used for IBD, rheumatoid arthritis, ankylosing spondylitis, psoriasis
Rheumatoid arthritis “infilx” pain in “da limbs”
Target and use for: Natalizumab
Target is alpha 4 integrin
Used for Multiple sclerosis, Crohn disease
Notes: alpha 4 integrin is for leukocyte adhesion, also get risk of PML in patients with JC virus
Target and use for: Abciximab
Targets Glycoprotein IIb/IIIa
Used as an anti-platelet agent for prevention of ischemic complications in patients undergoing percutaneous coronary intervention
IIb times IIIa equals abSIXimab
Target and use for: Denosumab
Target is RANKL
Used for Osteoporosis; inhibits osteoclast maturation (mimics osteoprotegrin)
Notes: denOSumab affects OSteoclasts
Target and use for: Digoxin immune Fab
Target: digoxin
Used as the antidote for digoxin toxicity
Target and use for: Omalizumab
Target is IgE
Used for allergic asthma; prevents IgI binding to FceRI
Target and use for: Palivizumab
Targets RSV F protein
used for: RSV prophylaxis for high-risk infants
Notes: paliVIzumab for VIruses
Which complement pathway will clear antigen-antibody complexes (type 3 hypersensitivity)
Classical because it has C3 which clears complexes and classic pathway is activated by IgM and IgG (alternative pathway is not activated by IgM and IgG)
Microctotoxicity test:
Determines if donor and recipient have matching HLA-A, B, and C (MHC class I), prevents against immune response
A CD19+ cell is what type
it is a B cell
A CD 14+ cell is what type
macrophage
What do you use to do a paternity test?
Use allotypes from immunoglobulins. They show distinct patterns of inheritance but do not affect the action of the immunoglobulins
B cell is identified by what CD markers
CD 19, 20, 21
CD55 identifies
complement decay-accelerating factor: is on all hemopoietic and non hemopoietic cells: blocks MAC: low levels or absence leads to paroxysmal nocturnal hemoglobinuria
