Immunology

Question 1

What are the functions of a lymph node? What occurs in the primary and secondary follicles of a lymph node? Where are they located? The medulla? The paracortex?

Answer 1

nonspecific filtration by macrophages
B and T cell storage
immune response activation

Follicle is located in the outer cortex. It is the site of b cell storage and proliferation. The primary follicles are dense and dormant. Secondary follicles are acives and have pale germinal centers

The medulla has medullary cords and sinuses. Sinuses communicate with efferent lymphatics and contain reticular cells and macrophages

The paracortex is between the medulla and the follicles and houses T cells. It contains venules which T and B cells enter from the blood. It is not well developed in pts iwth Digeorge.

Question 2

What do the mediastinal LNs drain? Internal iliac? Para-aortic? Superficial inguinal? Popliteal? What dos the right lymphatic duct drain? Thoracic duct? To where?

Answer 2

Mediastinal=trachea and esophagus

internal iliac=lower rectum to anal canal, bladder, vagina, prostate

Para-aortic=uterus, testes, ovaries, kidneys

superficial inguinal=anal canal, skin below umbilicus, scrotum

Popliteal=dorsolateral foott, posterior calf

Question 3

What are the sinusoids of the spleen? Where are t cells found in spleen? B cells? Where is the marginal zone and what is located there? Function? What is the function of macrophages in the spleen?

Answer 3

Sinusoids are long vascular channels in red pulp with fenestrated barrel hoop BM.

T cells are in periarteriolar lymph sheath (PALS) in white pulp

B cells in follicles in white pulp

Marginal zone is right b/w red and white pulp. Where APCs capture blood born antigens for recognition by lymphocytes.

Macrophages in spleen remove encapsulated bacteria.

Question 4

Explain how splenic dysfnction can lead to susceptibility to encapsulated organisms? What are some organisms? What are some heme/lymph results post splenectomy?

Answer 4

It leads to decr. IgM leading to decr. complement activation leading to decr. C3b opsonization lead to incr. susc. to encaps. organisms

SHiNE SKiS

Strep pneumoniae
H. influenzae
Neisseria meningitidis
E. coli
Salmonella spp.
Klebsiella pneumo
Group B Strep

Howell-Jolly bodies (nuclear remnants)
Target cells
Thrombocytosis
Lymphocytosis

Question 5

What is the function of the thymus? From what is it derived? What is the cortex like? What occurs there? medulla? What occurs there?

Answer 5

T cell differentiation and maturation.
third pharyngeal pouch
Cortex is dense with immature T cells (positive selection)
Medulla is pale wiht mature t cells and hassall corpuscles (negative selection).

Question 6

Compare and contrast innate immunity and adaptive immunity concerning components, mechanism, resistance, response to pathogens, physical barriers, secreted proteins, and key features in pathogen recognition.

Answer 6

INNATE

Complement, neutrophils, NK cells, Macrophages, monocytes, dendritic cells

Germline encoded

Resistance persists through generations

Nonspecific and rapid response

Skin, cilia

Lysozyme, complement, CRP, and Defensins are secreted

TLRs recognize PAMPs such as LPS, flagellin, and ssRNA

ADAPTIVE

B cells and T cells

Variation through V(D)J recombination

Resistance not heritable

Highly specific response, refined over time. Memory response.

No physical barriers

Immunoglobulins secreted

Memory cells: activated T and B cells—>subsequent exposure leads to stronger, quicker response

Question 7

What genes encode MHC? Compare and contrast the two MHC molecules concerning Loci, binding proteins, cellular location, function, antigen loading mechanism, structure, and associated proteins

Answer 7

HLA genes

MHC I

HLA-A,B,C

TCR AND CD-8

all nucleated cells

present endogenously synth. proteins to CD8+ cytotoxic t cells

antigen peptides loaded onto MHC I in RER after delivery via TAP

Beta 2 microglobulin

An alpha chain associated with a beta 2 microglobulin

MHC II

HLA-P,Q,R

TCR AND CD-4

APCs

Present exogenously synth antigens to helper T cells

Antigen loaded following release of invariant chain in acidified endosome

invariant chain

an alpha and a beta chain

Question 8

Which diseass are associated with HLA-A3, B27, DQ2/DQ8, DR2,DR3, DR4, DR5

Answer 8

A3=hemochromatosis

B27=seronegative arthropathies (psoriatic arthritis, ankylosing spondylitis, arthrithis of IBD, and Reactive Arthritis

DQ2/DQ8=celiac disease

DR2=MS, hay fever, SLE, Goodpasture

DR3=DM-I, SLE, Graves, Hashimoto

DR4=RA, DM-I

DR5=pernicious anemia, Hashimoto

Question 9

What is the funciton of NK cells? What cytokines enhance their activity? What signals them to kill (2 mechanisms)?

Answer 9

Use perforin and granzyme to induce apoptosis of virally infected cells and tumor cells

IL-2, IL-12, IFN-alpha, IFN-beta

Exposure to nonspecific activation signal on target cell or absence of class I MHC

Antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activates the NK cell)

Question 10

What are the major funcitons of both B cells and T cells?

Answer 10

B CELLS

Recognize antigen-undergo somatic hypermutation to optimize antigen specificity
Produce antibody
Maintain immunologic memory

T CELLS

CD4+ T cells help B cells make antibodies and produce cytokines to recruit phagocytes and activate other leukocytes
CD8+ T cells directly kill virus infected cells
Delayed cell-mediated hypersensitivity (IV)
Acute and chronic cellular organ rejection

Question 11

What steps occur in the differentiation of T cells? Where do the steps occur? What cytokines determine what kind of helper T cell it will become?

Answer 11

T cell precursor formed in marrow

Double positive T cell in thymus cortex. Positive selection (T cells expressing TCRs capable of binding surface self-MHC molecules survive)

Medulla-Either CD4+ or CD8+. Negative selection (T celsl expressing TCRs with high affinity for self antigens undergo apoptosis)

CD4+ and CD8+ t cells migrate to LNs

In the lymph node, IL-12 converts a helper T cell into a TH-1 cell. IL-4 into a Th2 cell. IL-6 and TGF-beta into a Th17 cell.

Question 12

Compare and contrast Th1 and Th2 cells concerning what they secrete, function, how they’re activated, and how they’re inhibited. How do macrophages interact with helper T cells?

Answer 12

TH1 CELL

IFN-gamma

Activates macrophages and cytotoxic T cells

IFN-gamma and IL-12

IL-4 and IL-10

macrophages release IL-12–>Th1 cells which release IFN-gamma to stimulate macrophages

TH2 CELL

IL-4, 5, 10, and 13

Recruits eosinophils for parasite defense and promotes IgE production by B cells

Activated by IL-4

Inhibited by IFN gamma

Question 13

What is the function of cytotoxic T cells? Mechanism?

Answer 13

Kill virus infected neoplastic,, and donor graft cells by inducing apoptosis

Release cytotoxic granules containing preformed proteins (performin, granzyme B)

Question 14

What is the function of regulatory T cells? Markers? mechanism?

Answer 14

Help maintain specific immune tolerance by suppressing CD4 and CD8 T cell effector fucntions

CD3, 4, 25, and FOXP3

Activated T regs produce anti inflmmatory cytokines (IL-10, TGF-beta

Question 15

How are naive t cells activated? How does b cells activation and calss switching occur?

Answer 15

DC sampls and processes antigen, migrates to the draining LN

Presents antigen on MHCII or MHC I and presented to CD4 or CD8 pos. cels

Costimulation provided by interaction b/w B7 and CD28 for CD4 cells and by IL-2 (from CD4 Th1 type cells) for CD8 cells

B CELL

Th- cell activation as above

B cell acts as an APC, presents antigen on MHC II

CD40 receptor on B cells binds CD40L on Th cell

Th cell secretes cytokines that determine Ig class switching of B cell. Be cells activates and undergoes class switching, affinity maturation, and antibody production

Question 16

What are the parts of an antibody? What are the functions of the different parts? What are 3 functions of antibodies? How is antibody diversity generated (4 things)?

Answer 16

Fab portion-binds antigen. determines idiotypes (which antigen it binds)-Heavy chain and light chain

Fc portion-constan. complement binding (closest to the Fab portion) and macrophage binding (furthest from Fab). Determines isotype

DIVERSITY

Random recombination of VJ (light) or V (D) J chains (heavy)
Random combination of heavy chains with light chains
Somatic hypermutation following antigen stimulation
Addition of NTs to DNA during recombination

FUNCTION

opsonization, neutralization, and complement activation

Question 17

What antibodies to mature B cells express on their surface. Where does isotype switching occur? What are the functions/unique characteristics of IgG, IgA, IgM, IgD, and IgE?

Answer 17

Mature B cells express IgD and IgM. Isotype switching occurs in germinal centers

IgG is the main antibody in secondary delayed response to an antigen. Most abundant in serum. Crosses placent. Fixes complement. Opsonizes bacteria, neutralizes bacterial toxins and viruses

IgA prevents attachment of microbes to mucous membranes. Does not fix complement. It is a monomer in circulation but a dimer when secreted. It is produced in the GI tract (Peyers patches) and protects against gut infections (giardia). Released into secretions (tears, saliva, mucus) and breastmilk)

IgM is produced in the primary (immediate) response to antigen. It fixes complement. Does not cross the placenta. It is the antigen receptor on the surface of b cells. Monomer on B cell. Pentamer when secreted. Pentamer enables avid binding to antigen while humoral response evolves

IgD=unclear function

IgE=binds mast cells and basophils. Cross links when exposed to allergen, mediating immediate (type I) hypersensitivity through release of inflammatory mediators such as histamine. Mediates immunity to worms by activating eosinophils.

Question 18

What are thymus-independent antigens? Thymus dependent? Results?

Answer 18

Indep=lack a peptide component (LPS) so they cannot be presented by MHC to T cells. Weakly or non-immunogenic; vaccines require boosters and adjuvants (pneumo polysaccharide vaccine)

Dep=contain a protein component. Class switching and immunologic memory occr as a result of B cell/Th cell interaction

Question 19

What are acute phase reactants? What produces them? Induces them? Which acute phase reactants are positive (upregulated)? Negative? What is their function?

Answer 19

Factors whose serum conc. change significantly in response to inflammation. Produced by liver in acute and chronic inflamm. states. Induced by IL-6

POSITIVE

CRP=opsonin
Ferritin=Binds and sequesters iron (so microbes can’t get to it)
Fibrinogen=coag factor; promotes endothelial repair. Correlates with ESR
Hepcidin=prevents release of iron bound to ferritin (anemia of chronic disease)
Serum amyloid A=can lead to amyloidosis

NEGATIVE

Albumin=reduction conserves AAs
Transferrin=Internalized by macrophages to sequester iron.

Question 20

Explain the 3 activation pathways for complement?
What are the functions of C3b, C3-5a, C5a, C5b-9? What are the opsonins? What are the inhibitors of the complement pathway? Briefly describe the steps of the complement pathway.

Answer 20

Classic=IgG or IgM (GM makes classic cars)
Lectin pathway-mannose or other sugars on microbes
Alternative pathway=microbe surface molecules

ALTERNATIVE

C3 leads to C3b to which Bb is added on, causing C3 to be converted to C3b and C3a.

CLASSIC

C1 converts C4 and C2 to C4a and C4b and C2a and C2b.
C4b2b make up the C3 convertase which converts C3 to C3a and C3b

LECTIN

Instead of C1, there is a C1 like complex

C3b makes up the C5 convertase complex which converts C5 to C5a and C5b
C5b joins with C6-9 to make up the MAC complex leading to lysis/cytotoxicity

FUNCTIONS

C3b=opsonin
C3a-5a=anaphylaxis, activation of mast cells—>histamine then LTs
C5a-neutrophil chemotaxis
Opsonins=C3b and IgG
Inhibitors=Decay accelerating factor and C1 esterase inhibitor

Question 21

What are the symptoms of C1 esterase inhibitor deficiency? Contraindications?

Answer 21

Hereditary angioedema.

ACE inhibitors

Question 22

What does C3 deficiency lead to?

Answer 22

Increased risk of severe, recurrent, pyogenic sinus and resp. tract infections.

Incr. susc to Type III HSRs

Question 23

C5-C9 deficie?

Answer 23

Neisseria bacteremia

Question 24

DAF (GPI anchored enzyme) deficiency?

Answer 24

Complement mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria.

Question 25

Which cytokines are secrted by macrophages? Functions?

Answer 25

IL-1=Fever, acute inflammation, activates endothelium to express adhesion molecules. Recruits WBCs thorugh chemokine secretion induction IL-6=Fever and acute phase reactants IL-8=Major chemotactor factor for neutrophils (clean up on aisle 8) IL-12=different. of T cells into Th1 cells. Activates NK cells TNF-alpha=mediates septic shock. Activates endothelium. Causes WBC recruitment, vascular leak (Cachexia)

Question 26

What cytokines are released by ALL T cells? Th1 cells specifically? Th2 cells? Functions?

Answer 26

ALL IL-2=growth of helper, cytotoxic, t regs and nk cells IL-3=growth and differenation of bone marrow stem cells. fucntions like GM-CSF TH1 CELLS IFN-gamma=actiaves macrophages and nk cells TH2 CELLS IL-4=differentiation into Th2 cells. Growth of B cells. To IgG and IgE IL-5=differn. of B cells. To IgA. Growth and differen. of eosinophils IL-10=modulates inflammatory response. Decreases MHC class II and Th1 cytokies. Inhibits activated macroph. and DCs. Also secreted by T regs. TGF-beta and IL-10 atTENuate the immune response.

Question 27

Explain the resp. or oxidative burst? What are the steps? How is NADPH involved of the clean up of ROS?

Answer 27

NADPH oxidase converts O2 to superoxide Superoxide dismutase converts superoxide to H2O2 H2O2 can be converted to H20 and O2 by catalase It can be converted to HOCl by Myeloperoxidase It can be taken up into a neutrophil and and converted to H20 by Glutathione peroxidase which is able to work because of NADPH's work with glutathione reductase.

Question 28

What are interferons alpha and beta? What are their functions?

Answer 28

Glycoproteins produced by virally infected cells that act loccally on uninfected cells priming them for a viral attack (basically killing them so the virus can't spread.

Question 29

What are the cell surface proteins on all T cells? Helper T cells? Cytotoxic T cells? T regs? B cells? Macrophages? NK cells? Hematopoetic stem cells?

Answer 29

T cells=TCR, CD3, CD28 helper t cells=CD4, CD40L cytotoxic t cells=CD8 Tregs=CD4, CD25 FOXP3 B cells=CD19-21, MHCII, B7, Ig, CD40 Macrophages=CD14, CD40, MHC-II, B7, Fc and C3b receptors NK cells=CD16 AND CD56 HSCs=CD34

Question 30

What is anergy.

Answer 30

A state during which a cell cannot become activated by exposure to antigen. Happens when a t cell encounters an antigen without a costimulatory signal. Self-tolerance.

Question 31

How do superantigens work? Endotoxins/LPS?

Answer 31

Superantigens cross link the beta region of TCR to the MHC class II on APCs. Unspecific, massive activation and release of cytokines Endotoxins/LPS=directly stimulate macrophages by binding to endotoxin receptor TLR4/CD14. Th cells not involved.

Question 32

Exposures to what microbes and toxins warrant passive immunization?

Answer 32

To Be Healed Very Rapidly Tetanus toxin, Botulinum toxin, HBV, Varicella, or Rabies virus

Question 33

Compare and contrast live attenuated and inactivated or killed vaccine concerning their general features, pros/cons, and examples.

Answer 33

LIVE ATTENUATED Microbe loses pathogenecity but maintains ability to transiently grow. Cellular and humoral response. MMR only vaccine given to persons with HIV Pros; Strong, lifelone immunity Cons:May revert to virulent form. Often contraindicated in pregnancy and immunodeficiency Measles, mumps, rubella, polia (Sabin), influenza (intranasal), varicella, and yellow fever KILLED Pathogen inactivated by heat or chemicals. Must maintain epitoope structure on surface antigens. Mainly a humoral response. Pros: Safer Cons: weaker immune response; booster shots usually required. R.I.P. Always Rabies, Influenza (injection), Polio (salk), Hepatitis A

Question 34

Describe a Type I HSR. Test used?

Answer 34

IgE on presensitized mast ells and basophils are cross linked. Release histamines which act on postcapillary venules. Reaction develops rapidly. There is a delayed response due to delayed release of leukotrienes Skin test for specific IgE

Question 35

Describe a Type II HSR. Tests used?

Answer 35

Cytotoxic-antibody mediated. IgM, IgG bind to fixed antigen on enemy cell leading to destruction (opson, complement mediated, and antibody mediated) Direct Coombs=detects antibodies that have already bound to patients RBCs Indirect Coombs=detects Abs that can adhere to other RBCs.

Question 36

Decribe a type III HSR? Tests? Describe the pathophys and symptoms of serum sickness and arthus reaction.

Answer 36

Antigen-antibody complexes activate complement, attracting neutrophils which release lysosomal enzymes. Immunoflourescent staining Serum sickness-Immune complex disease in which Abs to foreign proteins are produced. complexes form and are deposited in membranes. Caused by drugs acting as haptens. Fever, urticaria, arthralgia, proteinuria, lymphadenopathy (5-10 days) Arthus=local, subacute antibody-mediated HSR. Intradermal injection leading to complexes in skin. E Edema, necrosis, and activation of complement

Question 37

Describe Type IV HSR. What are 4 examples of when they occur? Tests?

Answer 37

T cell mediated. Sensitized T cells encounter antigen and release cytokines leading to macrophage activation. Cell mediated, not transferred by serum 4T's=T cells, transplant rejections, TB skin tests, Touching (contact dermatitis) Patch test, PPD

Question 38

Describe the pathogenesis and clinical presentation of the 4 types of blood transfusion RXNs, allergic reaction, anaphylactic reaction, febrile nonhemolytic reaction, and acute hemolytic transfusion reaction.

Answer 38

ALLERGIC Type I HSR against plasma proteins in transfused blood. Urticaria pruritus wheezing fever. Treat with antihistamines. ANAPHYLACTIC RXN severe allergic reaction. IgA-deficient individuals must receive IgA defiencet blood Dyspnea, bonchospasm, hypotension, resp. arrest, shock. Treat with epinephrine FEBRILE NONHEMOLYTIC TRANSFUSION RXN Tyype II HSR. Host Abs agianst donor HLA antigens and WBCs fever, headaches, chills, flushing ACUTE HEMOLYTIC TRANSFUSION RXN Type II HSR. Intravascular hemolysis (ABO) or extravascular hemolysis (host antibody reaction vs. donor RBCs Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinuria, jaundice

Question 39

What are 3 b cell immunodeficiencies? What is the defect, presentation and lab findings in each?

Answer 39

X-linked (Bruton) Agammaglobulinemia Defect in BTK, a tyrosine kinase--->no b cell maturation; x linked recessive Recurrent bacterial and enteroviral infections after 6 months Absent b cells in peripheral blood. Decr. Ig of all classes. Absent/scanty LNs and tonsils. SELECTIVE IGA DEFIC. Unknown defect. Most common immunodefic. ``` Majority are asymptomatic Airway and GI infections Autoimmune disease Atopy Anaphalaxis to IgA containing products ``` Descreaced IgA with normal IgG and IgM COMMON VARIABLE IMMUNODEF. Defect in B cell differentiation Can be acquired in 20s to 30s Incr. risk of autoimmune, bronchiectasis, lymphoma, sinopulmonary infections

Question 40

What are 4 t cell immunodeficiencies? What is the defect, presentation and lab findings in each?

Answer 40

THYMIC APLASIA (DIGEORGE) 22q11 deletion, no 3rd/4th pharyngeal pouch, absent thymus and parathyroids Tetany recurrent viral/fungal infections conotruncal abnormalities Decr. t cells, decr. PTH, decr. Calcium Absent thymic shadow 22q11 deletion on fish IL-12 RECEPTOR DEFIC. Decr. Th1 response. Disseminated mycobacterial and fungal infections May present after BCG vaccine (TB) Decr. IFN gamma AUTOSOMAL DOMINANT HYPER IGE SYNDROME (JOB) Defic. of Th17 cells due to STAT3 mutation leading to impaired recruitment of neutrophils to sites of infection FATED: course Facies, cold (noninflamed) staph Abscesses, retained primary Teeth, incr. IgE, Dermatologic problems (eczema) CHRONIC MUCOCUTANEOUS CANDIDIASIS T cell dysfunction, many causes Noninvasive candida albicans infections of skin and mucous membranes absent in vitro t cell prolifer. in response to c. albicans absent cutaneous reaction to candida antigens

Question 41

What are 4 t and b cell immunodeficiencies? What is the defect, presentation and lab findings in each?

Answer 41

SCID Several types including defective IL-2R gamma chain, adenosine deaminase deficiency Failure to thrive, chronic diarrhea, thrush. recurrent viral, bact., fugal, and protozoal infections Treatment: Bone marrow transplant Decr. T cell receptor excision circles (TRECs) Abscence of thymic shadow, germinal centers, and T cells ATAXIA TELANGIECTASIA ATM gene, failure to repair DNA double strand breaks--->cell cycle arrest Cerebellar defects, spider angiomas, IgA deficiency Incr. AFP Decr. IgA, IgG, and IgE Lymphopenia, cerebellar atrophy HYPER IGM SYNDROME Defective CD40L on Th cells, no class switching Severe pyogenic infections early in life. Opportunistic infections with Pneumocystis, cryptosporidium, and CMV Incr. IgM Decr. IgG, IgA, IgE Wiskott-Aldrich WAS gene, t cells unable to reorganize actin cytoskeleton WATER: Wiskott-aldrich, thrombocytopenic purpura, eczema, recurrent infections Incr. risk of autoimmune disease and malignancy Decr. to normal IgG and IgM Incr. IgE and IgA Fewer and smaller platelets

Question 42

What are 3 phagocyte immunodeficiencies? What is the defect, presentation and lab findings in each?

Answer 42

LEUKOCYTE ADHESION DEFICIENCY (TYPE 1) LFA-1 integrin (CD18) protein on phagocytes. Impaired migration and chemotaxis Recurrent bacterial skin and mucosal infections, absent pus formation, impaired wound healing, delayed separation of umbilical cord (30 days) Incr. neutrophils, absence of neutrophils at infeciton site CHEDIAK HIGASHI Lysosomal trafficing regulator gene (LYST) Microtubule dysfunction in phagosome-lysosome fusion Pyogenic infections by staph and strep partial albinism, peripheral neuro progessive neurodegen infiltrative lymphohistiocytosis Giant granules in granulocytes and platelets pancytopenia mild coag defects CGD defect of NADPH oxidase leads to less ROS and decr. oxidative burst in neutrophils Incr. susc. to catalase positive organisms Need PLACESS nocardia, pseudomonas, listeria, aspergillus, candida, e. coli, s. aureus, serratia Abnormal dihydrorhodamine Nitroblue tetrazolium dye reduction test is neg.

Question 43

Describe 4 types of transplant rejections including when the onset is, what the pathogenesis is, and what symptoms are present.

Answer 43

HYPERACUTE within min. pre-existing antibodies react to donor antigen and activate complement widespread thrombosis of graft vessels--->ischemia and necrosis Must remove graft ACUTE weeks to months Cellular: CD8+ T celsl activated against donor MHC Humoral: similar to hyperacute except antibodies develop post transplant Vasculitis of graft vessels with dense interstitial lymph. infiltrate Immunosuppressants CHRONIC months to years CD4+ T cells respond to recipient APCs presenting donor peptides including allogeneic MHC Both cellular and humoral components Recipient T cells react and secrete cytokines leading to proliferation of vascular smooth muscle and parenchymal fibrosis. Arteriolosclerosis GVHD Varies Grafted immunocompetent t cells proliferate in the immunocompromised host and reject host cells with foreign proteins leading to severe organ dysfunction Maculopapular rash, jaundice, diarrhea, HSM Usually in bone marrow and liver transplants Potentially beneficial in bone marrow transplant for leukemia