BIOL 0530 Immunology Module 3

What is another name for a neutrophil?

Polymorphonuclear leukocyte

What is the most common white blood cell (leukocyte), what is the most common result of its recruitment to the site of an injury?

Neutrophil, inflammation

What are the five hallmarks of inflammation?

Heat, redness, swelling, pain, and loss of function

Why do cells recirculate? What cells recirculate and what cells do not?

Surveillance (^change of Ag contact), lymphocytes, neutrophils

What does neutrophils to not being able to recirculate mean? Why do they not need to recirculate?

Won’t return to blood stream after extravasation, not Ag specific (innate), only for killing

What cells line all blood vessels/capillaries, where are they located in relation to the vessels, and what is the result of their tight packing?

Endothelial cells, inside, blood vessels are waterproof

What is the morphology of the neutrophil nucleus and what is the composition of its granules?

Multi-lobed, antimicrobial proteins and toxic enzymes

What general role do endothelial cells play in inflammation?

Pro-inflammatory cytokines cause endothelial cells near injury to express selectins and integrins

What are the four steps that lead to extravasation and why do lymphocytes/neutrophils do it?

Rolling, activation, arrest/adhesion, transendothelial migration, function within tissue not blood

What do integrins mediate and what do selectins mediate?

Adhesion, rolling and cell interactions

Where are E, L, and P selectins found?

Activated endothelial cells, activated leukocytes, activated leukocytes, endothelial cells, and platelets

Which is stronger: selectin/selectin ligand binding or integrin/integrin ligand binding?

Integrin/integrin ligand

What are the roles of chemokines in inflammation/extravasation?

Leukocyte migration, upregulate integrin/selectin expression

What is the physical structure of integrins, what conformations do they have, and what is the name of the integrin with ^^^expression on neutrophils?

Heterodimer with alpha/beta chains, inactivated and activated, Mac1

What causes the conformational change of integrins from their inactivated to activated conformation?

Chemokine binding to chemokine receptor

What happens in a single and double knockout for selectins? What is an additional effect of that knockout?

Reduced extravasation, no extravasation, less integrins (selectin binding activates integrin expression)

What defect causes leukocyte adhesion deficiency 1 (LAD-1), what happens to neutrophils, what are the results, and what is a common treatment?

Integrin expression (like MAC-1), ^in blood (rolling but not adhesion), ^bacterial infections, bone marrow transfusion

What is Natalizumab, what is its target, what diseases can it treat, and why is it dangerous?

A mAb for organ-specific diseases caused by ^inflammation, integrins, Crohn’s (gut) and MS (brain), immunosuppression risks fatal infections

What cells bind to high endothelial venule and what cells don’t?

Lymphocytes, neutrophils

What are the different bindings that occur in normal endothelium and HEV?

PSGL-1 on neutrophil binds P-selection on endothelial (rolling), L-selection on T-cells binds CD34 on HEV in lymph nodes

What causes T and B cells sorting to their correct zones?

T cells express CCR7, B-cells don’t

What are the three steps for T-cell extravasation into the lymph nodes?

T-cell L-selection binds HEV sialomucin (rolling), T-cell CCR7 binds CCL21 (chemoattractant) expressed by HEV, CCR7 binding activates LFA1 (integrin) expression (adhesion to HEV)

What is the homing concept and what is an example?

Receptor specificity and chemokines send different cells to different places, T-cells can be skin-homing or mucosal-homing due to receptor/ligand expression

What is chemotaxis?

Mobile response of a cell towards a chemical that attracts it

When does integrin activation occur in the lead up to extravasation? What are the two different kinds of activation?

After rolling, before adhesion, inside-out and outside-in

What are the things that are tested for in newborn blood to test for primary immunodeficiencies?

Ab levels, leukocytes levels, TCR excision circle levels (product of TCR gene rearrangment)

What are the four types of primary immunodeficiencies?

Combined (T-cell + other), B-cell/Ab, innate, immune regulators

What variety of combined immunodeficiency is caused by dejects in VDJ recombination? What are examples of things that can cause those defects?

No T-cells or B-cells but can have NK cells, Rag1/2, Artemis, and ligase defects

What are five kinds of combined immunodeficiencies?

SCID, bare-lymphocyte syndrome, DiGeorge’s syndrome, Hyper IgM (X-linked), WAS (X-linked)

Defects in the genes for what proteins cause SCID? What are the clinical outcomes?

DNA-PKcs, Rag1/2, Artemis, IL2R-gamma, and others, T-cells absent, B-cells and NK cells may be absent or lessened

What is the overall and 5 specific components of the immunobiology of SCID?

Targets early lymphocyte development, defective differentiation of HSCs, purine metabolism, gene rearrangement (Rag1/2), cytokine signaling (T-cell progenitors), and signaling (pre-TCR/TCR)

Defects in the genes for what proteins cause bare lymphocyte syndrome? What are the clinical outcomes?

MHC class 2 transcription factors or TAP, lack of APC activity causes impaired peripheral T-helper and ^infections (MHC class 2) and ^viral/bacterial lung infections and NK cell skin lesions (MHC class 1)

What is the immunobiology for the two varieties of bare lymphocyte syndrome?

No MHC class 2 (lack of CD4+ T-cell activation) or no MHC class 1 cell surface expression (impaired selection for CD8+ T-cells)

What is TAP, what is the function of TAP, and what immunodeficiency does it cause?

Transport associated protein, exports MHC class 1 + Ag to surface, bare-lymphocyte syndrome (combined)

Defects in what genes cause DiGeorge’s syndrome? What are the clinical outcomes?

Deletions on chromosome 22 (including TBX1), lack of T-cells and low B-cells/Ab (^infections due to lack of adaptive)

What is the immunobiology of Digeorge’s syndrome?

Developmental defects of thymus, facial features, heart, and learning disabilities

Defects in the genes for what proteins cause Hyper IgM syndrome? What are the clinical outcomes?

CD40L (X-linked), ^bacterial infections/diarrhea, failure to thrive, low neutrophils, autoimmunity

What is the overall and three specific components of the immunobiology of Hyper IgM syndrome?

Impaired T-cell/B-cell or APC communication (Ab for TI-Ag unaffected), limited Ab for T-cell dependent Ag, no isotype switching (only IgM), less T-cell activation/memory cells

What does WAS stand for, what defect in a gene causes it, and what does that gene code for?

Wiskott-Aldrich syndrome (X-linked), WASP gene, cytoskeletal protein in hematopoietic cells

What are the clinical outcomes of WAS?

Eczema, thrombocytopenia (bleeding), ^bacterial infections, autoimmunity, B-cell malignancy

What is the immunobiology of WAS?

WASP normally aids in cell migration, actin polymerization, and leukocyte signal transduction, defect causes impaired Ab and cell-mediated immunity

What are the three kinds of B-cell/Ab immunodeficiencies?

Hyper IgE (Job) syndrome (autosomal dominant), X-linked agammaglobulinemia, selective IgA deficiency

What is the defect that causes Hyper IgE syndrome and what is the resulting immunobiology?

STAT3 gene mutation (STAT3 deficient), T-helper pathway dysregulation (low T-helper 17 and high IgE)

What is GAS, what immunodeficiency is it involved in, and how?

Gamma interferon activation site, Hyper IgE syndrome, ???

Defect in the gene for what protein causes X-linked agammaglobulinemia and what does it normally do?

Btk, pre-BCR signal transduction after heavy chain rearrangement,

What is the immunobiology of X-linked agammaglobulinemia and what are the clinical outcomes?

Very low Ab (B-cells are stuck immature in bone marrow), ^bacterial infections (treat with passive Ab/antibiotics)

Defects in the genes for what proteins causes Selective IgA deficiency and what is the resulting immunobiology?

B-cell regulatory proteins, constant region, or other unknown, no IgA plasma cells (other isotype levels normal)

What are the clinical outcomes for Selective IgA deficiency?

Vary from asymptomatic to ^respiratory/genitourinary bacterial infections

What are the five kinds of innate immunodeficiencies?

LAD, chronic granulomatous disease, Chediak-Higashi syndrome, complement (Lupus, MBL, PNH), NK deficiency

Defect in the gene for what protein causes leukocyte adhesion deficiency (LAD)? What is the resulting immunobiology?

Beta chain of LFA-1 and MAC-1 integrins, limited leukocyte recruitment to inflamed areas (neutrophil extravasation to fight infection)

What are the clinical outcomes of LAD? Life expectancy?

^fungal and bacterial infections, 24 months

Defect in the gene for what protein causes chronic granulomatous disease? What is the resulting immunobiology?

Phagosome oxidase (PHOX) proteins (Mainly X-linked but also autosomal recessive), defective NADPH oxidase pathway to generate ROS in phagocytes

What are the clinical outcomes of chronic granulomatous disease?

^bacterial/fungal infections, ^inflammation (improper clearance), granulomas encase pathogens

Defect in the gene for what protein causes Chediak-Higashi syndrome? What is the resulting immunobiology?

LYST (lysosomal trafficking regulator), defective microtubule function prevents phagolysosome fusion

What are the clinical outcomes of Chediak-Higashi syndrome?

^bacterial infections, defective blood clotting, pigmentation, neurological function

What are the general genetic causes, immunobiology, and clinical outcomes for complement deficiencies?

Any genes/pathways for complement activation, failure to activate complement, ^bacterial/fungal infections, autoimmunity (improper immune complex/cell debris clearance)

What complement deficiency does Lupus correlate with and how?

C4 and C1q, C4 needed for C3 convertase, less C3b = less opsonization = less immune complex clearance = ^inflammation + infections

What are the clinical outcomes of MBL deficiency? What kind of immunodeficiency is it?

Varies from asymptomatic to ^childhood infections (5-10% of population), innate

Defect in what gene for what protein causes paroxysmal nocturnal hemoglobinuria? What is the resulting immunobiology and clinical outcomes?

PIG-A, GPI anchor (lipid), no DAF or protectin on RBC surface = complement attacks self-RBC, hemolytic anemia, venous thrombosis, and pancytopenia

What defects can cause NK deficiencies and what is the resulting immunobiology/clinical outcomes?

Many receptors/transcription factors/cell cycle factors, zero NK cells, ^viral infections/cancer

What are the two kinds of immune regulator deficiencies?

APS-1 and IPEX syndrome (X-linked)

What does APS-1 stand for, a defect in what gene causes it, and what is the resulting immunobiology?

Autoimmune polyendocrine syndrome, AIRE gene, impaired self-Ag presentation by mTECs during T-cell development leads to organ-specific autoimmunity

What are the clinical outcomes of APS-1?

Autoimmunity, impaired endocrine function, ^fungal infections

What does IPEX syndrome stand for, a defect in what gene causes it, and what is the resulting immunobiology?

Immune dysregulation, polyendocrinopathy, and X-linked syndrome, inactivated FoxP3, zero T-regulatory cells (autoreactive T-cells go unchecked)

What are the clinical outcomes of IPEX syndrome?

Autoimmunity (immune destruction of bowel/pancreas/thyroid/skin, deadly)

What are the three general outcomes that immunodeficiencies are linked to?

Cancer, autoimmunity, ^infections

What are the four ways that primary immunodeficiencies can be treated?

Replace protein (passive Ig or recombinant protein like rIFN-gamma injection), replace cell type/lineage/organ (bone marrow/HSC transplant, thymic transplant treats Digeorge’s), replace gene (gene therapy with CRIPSR), and antibiotics/antifungals

What are the three mouse models and what are the general applications to research of animals?

Nude, SCID, and RAG K/O mouse, cancer/HIV/organ transplant research and hybridoma = Ab production

Mutation of what gene creates Nude mice and what are the resulting clinical outcomes?

Foxn1 (recessive on chromosome 11), no T-cells or T-dependent B-cells, hairless with vestigal thymus

Mutation of the gene for what protein creates SCID mice, what protein does it make, and what are the resulting clinical outcomes?

PRKD, DNA-PK protein, no mature lymphocytes (immature still present), single K/O may still produce Ab (leaky mutation)

Mutation of the gene for what protein creates the RAG K/O mice and what are the resulting clinical outcomes?

Loss/impaired Rag1/2, //insert

What are the four kinds of secondary immunodeficiencies?

Agent-induced, acquired hypogammaglobulinemia, HIV/AIDS, measles/immune amnesia

What is the cause of agent-induced immunodeficiency?

Environmental agents, cytotoxic drugs or irradiation for cancer

What is the cause for acquired hypogammaglobulinemia? What is the resulting immunobiology?

No known genetic link, low immunoglobulin but normal T-cells

What causes AIDS, what are its features, and what viruses are similar?

HIV-1 retrovirus, two RNA genome segments, simian/feline/bovine immunodeficiency virus and mouse leukemia virus

What is the pathology of HIV?

Attaches to CD4+ and a coreceptor (CCR5 for macrophages or CXCR5 for T-cells), infiltrates cells, reverse transcriptase turns RNA into DNA, integrase enzyme integrates the viral DNa into the human genome

What receptor on dendritic cells enables HIV pathology?

DC-sign on dendritic cells in vagina/rectum shares HIV particle w/ T-cells/macrophages

What are the criteria for AIDS?

HIV infection, <200 CD4+ T-cells per uL of blood or opportunistic infections

What are the opportunistic infections associated with AIDS?

Candidiasis (trachea/bronchi/lungs), cervical cancer, Kaposi’s sarcoma, lymphoma, toxoplasmosis (brain), progressive multifocal leukoencephalopathy, mycobacterium tuberculosis, pneumonia

What does HAART stand for, what does it target, and why is it better than individual drugs?

Highly active antiretroviral therapy, integrases and proteases, high mutation rate allows survival against one drug at a time

What are PrEP and PEP, what do they stand for, and when is it used?

Preventative measures for HIV, pre-exposure prophylaxis or post-exposure prophylaxis, before or after dangerous sex or drug use

What are the difficulties of producing an HIV vaccine?

Rapid virus mutation, many strains/subtypes in blood, virus DNA integration into human genome, good animal models are rare, need mucosal immunity (mucus can harbor HIV) and testing attenuated vaccines is dangerous

How long does the measles virus affect immune memory for?

5 years

What parts of the immune system do HIV and measles cause deficiencies in?

T-cells and antibodies

Who coined the term anaphylaxis, to describe what, and after what expirement?

Charles Richet and Paul Portier, something that induces a stronger negative response with each exposure, man o’ war reaction in dogs

What are hypersensitivities?

^immune response with adverse effects that require prior exposure

What are the four kinds of hypersensitivities?

Allergic anaphylaxis and atopy, antibody, immune complex, and delayed

What are the main characteristic of a type 1 hypersensitivity, what is it associated with, and what percentage of people have it?

IgE dominated (Th2, mast cells), asthma, allergies, atopy (predisposition for allergic hypersensitivities), 30% adults 40% children

What are some results of the immune amnesia/respiratory tract remodeling caused by measles?

Measles-associated encephalitis, pneumonia

What did the Prausnitz and Kustner test prove?

Produce wheal and flare allergic reaction with allergen + allergic person’s serum

Who built off of Prausnitz + Kustner test and how?

Elvin Kabat, Ab in serum

What built off of Elvin Kabat and Prausnitz/Kustner’s work with Type 1 hypersensitivities and how?

Ishizakas, identified the IgE fraction of serum

What are the characteristics of an atopic individual and the environmental antigens associated with them?

Predisposed to generate IgE against environmental Ag and have more Th2, Ag are proteins/glycoproteins with many epitopes that may mimic PAMPs or have enzymatic activities 

What are the receptors on mast cells with high affinity for IgE, how does IgE bind, and what is IgE half-life before and after binding?

Fc-epsilon-R1, cross-link receptors (activate mast cells), 2-3 days and 2 weeks

What are the resulting of mast cell activation by IgE?

Degranulation, cytokine production, lipid mediator production

What are the molecules made by innate immune cells that produce a type 1 hypersensitivity?

Hstimate, proteases, leukotrienes, prostaglandins, cytokines

What is histamine made from, what does it bind to, and how does it contribute to a type 1 hypersensitivity reaction?

Decarboxylated histidine (amino acid), one of four histamine receptors, contract smooth muscles (vomit/diarrhea/airway cut off), secrete mucus (runny nose), increase venule permeability (leak mucus)

What molecules accounts for 10% of granulocyte granule components by weight?

Histamine

What is are the features of prostaglandins and leukotrienes and how do they contribute to a type 1 hypersensitivity reaction?

Bioactive lipids (cleaved membrane phospholipids are potent effectors), ^^airway cut off than histamine, ^vascular permeability, cause pain, recruit and activate leukocytes

What are some of the chemokines and cytokines produced by basophils/eosinophils/mast cells that contribute to type 1 hypersensitivity reactions?

IL-4 and IL-13 (^Th2 = ^IgE), IL-5 (recruits/activates eosinophils), TNF-alpha (shock in anaphylaxis), IL-8 (chemotactic factor, attract cells), GM-CSF (production/activation of myeloid cells including granulocytes)