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STEP1 > Immunology > Flashcards

Immunology Flashcards

1
Q

Describe the flow of lymph through a lymph node.

A

from the afferent vessel to a subcapsular sinus to a trabecular sinus in the cortex to a medullary sinus and then out the efferent vessel

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2
Q

What are the major components of the cortex, paracortex, and medulla of a lymph node.

A
  • cortex: B-cell follicles
  • paracortex: T-cells
  • medulla: cords of plasma cells and sinuses containing histiocytes and reticular cells
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3
Q

Give the structures drained by each of the following lymph node clusters:

  • cervical
  • hilar
  • axillary
  • mediastinal
  • celiac
  • superior mesenteric
  • inferior mesenteric
  • internal iliac
  • para-aortic
  • superficial inguinal
  • popliteal
A
  • cervical: head and neck
  • hilar: lungs
  • axillary: upper limb, breast, skin above umbilicus
  • mediastinal: esophagus and trachea
  • celiac: liver, spleen, pancreas, stomach, upper duodenum
  • superior mesenteric: lower duodenum, jejunum, ileum, colon to splenic flexure
  • inferior mesenteric: splenic flexure to upper rectum
  • internal iliac: lower rectum to pectinate line, bladder, middle ⅓ vagina, cervix, prostate
  • para-aortic: ovaries, testes, kidneys, uterus
  • superficial inguinal: vulva, scrotum, anal canal below pectinate line, skin below umbilicus
  • popliteal: posterior calf and dorsolateral foot
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4
Q

The stomach and upper duodenum are drained by which lymph node cluster?

A

the celiac

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5
Q

Splenic dysfunction leaves one susceptible to which group of organisms? Which organisms in particular?

A

encapsulated organisms (Please SHINE my SKiS):

  • P. aeruginosa
  • Streptococcus pneumoniae
  • H. influenza type b
  • N. meningitidis
  • E. coli
  • Salmonella spp.
  • Klebsiella pneumoniae
  • Group B Strep
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6
Q

What are Howell-Jolly bodies? What do they usually indicate?

A

basophilic nuclear remnants found in erythrocytes, often indicative of splenic dysfunction

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7
Q

List 4 hematologic findings consistent with splenectomy.

A
  • thrombocytosis
  • lymphocytosis
  • target cells
  • Howell-Jolly bodies
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8
Q

What is the splenic marginal zone?

A

an area between the red pulp and white pulp, which contains macrophages and specialized B cells, where APCs capture blood-borne antigens for recognition by lymphocytes

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9
Q

The thymus is derived from which embryonic structure?

A

the third pharyngeal pouch

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10
Q

The innate immune system relies on what system for pathogen recognition?

A

TLRs that recognize PAMPs

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11
Q

HLA genes encode what?

A

MHC molecules

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12
Q

Which HLA genes encode which MHC-I molecules? Which encode MHC-II?

A
  • MHC-I are encoded by HLA-A, B, C

- MHC-II are encoded by HLA-DP, DQ, DR

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13
Q

Which cells express MHC-I and MHC-II?

A

MHC-I are expressed by all nucleated cells while MHC-II are expressed only by antigen presenting cells

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14
Q

What is B2-microglobulin?

A

a protein without a transmembrane domain that is found in association with MHC-I alpha chains

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15
Q

What is invariant chain?

A

a protein that binds MHC-II prior to loading in order to prevent loading endogenous antigens during trafficking

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16
Q

Describe the process of loading MHC-I.

A
  1. MHC-I is synthesized in the RER
  2. TAP in the cytosol escorts endogenous antigens to the surface of the RER
  3. at the surface, TAP delivers the antigen to MHC-I
  4. now loaded, MHC-1 is trafficked to the plasma membrane
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17
Q

Describe the process of loading MHC-II.

A
  1. MHC-II is synthesized and bound to invariant chain
  2. MHC-II is delivered to an endosome where invariant chain is cleaved to form CLIP
  3. in the endosome, exogenous antigens outcompete CLIP for binding to MHC-II
  4. MHC-II is loaded with exogenous antigen and trafficked to the plasma membrane
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18
Q

Give the major disease associated with each of the following HLA subtypes:

  • A3
  • B8
  • B27
  • DQ2/8
  • DR2
  • DR3
  • DR4
  • DR5
A
  • A3: hemochromatosis
  • B8: addison disease, myasthenia gravis
  • B27: seronegative arthropathies (psoriatic arthritis, ankylosing spondylitis, IBD-associated arthritis, reactive arthritis)
  • DQ2/8: celiac disease (“I 8 2 much gluten at DQ)
  • DR2: MS, SLE, goodpasture
  • DR3: DMT1, SLE, Grave’s, Hashimoto thyroiditis, Addison disease
  • DR4: rheumatoid arthritis, Addison disease
  • DR5: pernicious anemia, Hashimoto thyroiditis
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19
Q

What is the strongest HLA-disease association?

A

HLA-B27 and ankylosing spondylitis

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20
Q

What is CD16?

A

an Fc receptor expressed by NK cells

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21
Q

What are the two targets/mechanisms through which NK cells kill?

A
  • ADCC of IgG-bound targets

- perforin/granzyme induced apoptosis of cells lacking MHC-I

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22
Q

List four cytokines that enhance the activity of NK cells.

A
  • IL-2
  • IL-12
  • IFN-a
  • IFN-B
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23
Q

Describe positive and negative selection of T cells.

A
  • in the thymic cortex, T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells survive (positive selection)
  • in the thymic medulla, T cells with a high affinity for self antigens expressed by epithelial reticular cells using AIRE undergo apoptosis (negative selection)
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24
Q

What is autoimmune polyendocrine syndrome 1? How does it present?

A
  • an autoimmune condition that results due to an AIRE loss of function mutation (a transcription factor needed for the expression of certain self-antigens by epithelial reticular cells in the thymus)
  • presents with hypoparathyroidism, adrenal failure, and chronic candida infections
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25
Q

What is AIRE? A loss of function mutation causes what disease?

A
  • a transcription factor needed by epithelial reticular cells in the thymus in order to express some self-antigens for the negative selection of T-cells
  • deficiency results in autoimmune polyendocrine syndrome 1
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26
Q

What is the purpose of regulatory T cells? How do they carry out this function and how can we identify them?

A
  • they help maintain peripheral tolerance by suppressing CD4 and CD8 T-cells
  • once activated they secrete two anti-inflammatory cytokines: IL-10 and TGF-B
  • they express the CD25 and FOXP3 immunophenotype
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27
Q

CD25 and FOXP3 are makers for what kind of immune cell?

A

regulatory T cells

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28
Q

List the three cell types that serve as APCs?

A
  • B cells
  • macrophages
  • dendritic cells
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29
Q

In addition to binding MHC-I/II, T-cells require what other signal in order to become activated?

A

B7 expressed by the APC must bind CD28 expressed by the T cell

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30
Q

What cell type expresses CD80/86 and what is it’s function?

A
  • also known as B7.1/2

- it binds CD28 expressed by T cells and serves as the second signal for activation in addition to binding MHC

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31
Q

What cell type expresses CD28 and what is it’s function?

A

expressed by T cells, it binds B7.1/2 (aka CD80/86) expressed by an antigen presenting cell, and serves as the second signal for activation in addition to binding MHC

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32
Q

What induces B-cell class switching?

A
  • B cell expresses MHC-Ag which is bound by TCR

- the T-cell also expresses CD40L, which binds CD40 expressed by B-cells and serves as the second signal

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33
Q

What cell type expresses CD40 and what is it’s function?

A

expressed by B cells, it binds CD40L expressed by T cells and serves as the second signal required for class switching

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34
Q

Immunoglobulins can be divided up into what two regions?

A

Fab (antigen binding fragment) and Fc (constant fragment)

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35
Q

Give four characteristics of the Fc region.

A

The 4 C’s:

  • constant
  • carboxy terminal
  • carbohydrate side chains
  • complement binding
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36
Q

Through what two mechanisms do we generate antibody diversity?

A
  • random combination of VJ (light-chain) and V(D)J (heavy-chain) genes
  • random addition of nucleotides to DNA during recombination
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37
Q

What is terminal deoxynucleotidyl transferase?

A

an enzyme that randomly adds nucleotides to DNA during recombination of the VJ and V(D)J genes to improve immunoglobulin diversity

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38
Q

Which immunoglobulin isotypes fix complement? Which region of those immunoglobulins does complement fix to?

A
  • IgM and IgG fix complement

- it fixes the Fc region of those immunoglobulins

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39
Q

Mature, naive B cells express what immunoglobulin isotypes on their surfaces?

A

IgM and IgD

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40
Q

IgG functions as an immune factor through what three mechanisms?

A
  • opsonizes bacteria
  • fixes complement
  • neutralizes bacterial toxins and viruses
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41
Q

How does IgA protect it’s host?

A

by preventing attachment of bacteria and viruses to mucous membranes

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42
Q

What is J chain?

A

a protein that binds the Fc region of IgA and IgM to form dimers and pentamers, respectively

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43
Q

IgA crosses epithelial cells by a process known as what?

A

transcytosis

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44
Q

What is secretory component?

A

a molecule, acquired from epithelial cells, that protects the Fc portion of IgA from proteases in the gut lumen

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45
Q

Which isotype of immunoglobulin is produced at the highest level in the human body? Which isotype reaches the highest serum concentrations?

A
  • IgA is most produced by doesn’t reach serum

- IgG is the most abundant isotype in serum

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46
Q

What is the purpose of IgE?

A

binds mast cells and basophils and cross-links when exposed to an allergen, thereby mediating a type I hypersensitivity

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47
Q

What are thymus-independent antigens?

A

those lacking a peptide component which cannot be presented by MHC to T cells and are therefore weakly immunogenic

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48
Q

Which isotype of immunoglobulin readily crosses the placenta?

A

IgG

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49
Q

What are acute-phase reactants? Where are they produced? They are notably induced by which cytokine?

A
  • factors whose serum concentrations change significantly in response to inflammation
  • produced in the liver
  • induced by IL-6
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50
Q

What is c-reactive protein? What is it’s immunologic function?

A

a positive (upregulated) acute-phase reactant that serves as an opsonin and fixes complement

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51
Q

List the five positive and two negative acute phase reactants.

A
  • positive: c-reactive protein, ferritin, fibrinogen, hepcidin, serum amyloid A
  • negative: albumin, transferrin
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52
Q

What purpose does ferritin serve as an acute phase reactant?

A

it is upregulated, binding and sequestering iron to inhibit microbial iron scavenging

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53
Q

What purpose does hepcidin serve as an acute phase reactant?

A

it reduces iron absorption (by degrading ferroportin) and reduces iron release from macrophages, thereby inhibiting microbial iron scavenging

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54
Q

The membrane attack complex is effective against which types of organisms?

A

gram negative bacteria, most notably Neisseria

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55
Q

What are the three complement pathways and what activates each?

A
  • classic: IgG or IgM mediated
  • alternative: microbe surface molecules
  • mannose: mannose or other sugars on microbe surface
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56
Q

Which complement components contribute to anaphylaxis via activation of mast cells?

A

C3a, C4a, C5a

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57
Q

Which complement components are part of the MAC?

A

C5b, C6-C9

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58
Q

What are the functions of C3b?

A
  • opsonization

- clear immune complexes

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59
Q

What are the functions of C5a?

A
  • anaphylaxis

- neutrophil chemotaxis

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60
Q

What are the two primary opsonins in the human body?

A

IgG and C3b

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61
Q

Describe the basic steps along the complement pathway.

A
  • a C3 convertase is formed which converts C3 to C3b
  • C3b helps form a C5 convertase
  • C5 convertase converts C5 to C5b
  • C5b joins with C6-C9 to form the MAC
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62
Q

What is decay-accelerating factor?

A

a glycophosphatidylinositol-anchored enzyme, aka CD55, that inhibits complement activation on self-cells

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63
Q

What is C1 esterase inhibitor?

A

an enzymes, that inhibits complement activation on self-cells

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64
Q

Review the full complement cascade.

A

See Lecture Notes

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65
Q

What is C1 esterase inhibitor deficiency? Describe the pathogenesis? What is the primary contraindication?

A
  • an AD disorder known as hereditary angioedema resulting form loss of the complement regulator
  • there is unregulated activation of kallikrein, leading to increased levels of bradykinin, as well as accumulation of anaphylatoxins, which results in swelling
  • ACE inhibitors are contraindicated because they can lead to bradykinin accumulation
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66
Q

Why are ACE inhibitors contraindicated in those with C1 esterase inhibitor deficiency?

A
  • the deficiency results in the accumulation of bradykinin, which then contributes to episodes of swelling
  • ACE inhibitors also lead to accumulation of bradykinin
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67
Q

C3 deficiency increases a person’s risk for what two things?

A
  • severe, recurrent, pyogenic sinus and respiratory infections
  • type III hypersensitivity reactions
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68
Q

A deficiency in C5-C9 increases one’s risk for what?

A

Neisseria bacteremia

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69
Q

How does decay-accelerating factor deficiency manifest?

A
  • DAF normally protects self-cells from complement fixation

- DAF deficiency causes complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria

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70
Q

What is lactoferrin? Where is it found?

A

a protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation

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71
Q

What are interferons and specifically what are they important for defending against?

A
  • they are glycoproteins part of the innate host defense against RNA and DNA viruses
  • they are synthesized by virus-infected cells and signal via autocrine and paracrine mechanisms to induce transcription of antiviral proteins that selectively degrade viral nucleic acid and inhibit viral protein synthesis
  • it up regulates RNase L, an endonuclease that degrades RNA and protein kinase R, which inactivates eIF-2 and inhibits initiation of translation
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72
Q

What pneumonic helps recall the functions of IL-1 through IL-6?

A

Hot T-bone stEAK

  • 1: hot (fever)
  • 2: stimulates CD8 T cells
  • 3: stimulates bone marrow (like GM-CSF)
  • 4: IgE production
  • 5: IgA production
  • 6: aKute-phase protein production
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73
Q

What is the function of IL-8?

A

recruit neutrophils

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74
Q

What are the two major functions of IL-12?

A
  • induce Th1 phenotype

- activate NK cells

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75
Q

Which cytokine mediates septic shock?

A

TNFa

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76
Q

What is the major function of TNFa?

A
  • it mediates septic shock by activating the endothelium for recruitment of WBCs and vascular leakage
  • responsible for cachexia in malignancy
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77
Q

What are the two major anti-inflammatory cytokines?

A

IL-10 and TGF-B

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78
Q

What is the major function of IL-10?

A

it is anti-inflammatory: decreases expression of MHC-II and Th1 cytokines, inhibits activated macrophages and dendritic cells

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79
Q

List the cell type(s) that express each CD:

  • CD3
  • CD16
  • CD21
  • CD25
  • CD28
  • CD34
  • CD40
  • CD40L
  • CD80/86 (B7.1/2)
  • CXCR4
  • CCR5
  • FOXP3
A
  • CD3: T cells
  • CD16: NK cells
  • CD21: B cells
  • CD25: regulatory T cells
  • CD28: T cells
  • CD34: hematopoietic stem cells
  • CD40: B cells
  • CD40L: helper T cells
  • CD80/86: APCs
  • CXCR4: T cells
  • CCR5: T cells and macrophages
  • FOXP3: regulatory T cells
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80
Q

What is the purpose of CD3 and which cells express it?

A

found on T cells, it is associated with the TCR for signal transduction

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81
Q

What is the significance of CXCR4 and CCR5?

A

they are the co-receptors for HIV found on T cells

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82
Q

What is the signficiance of CD34?

A

it is a marker of hematopoietic stem cells

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83
Q

Do B cells express CD40 or CD40L? CD28 or CD80/86?

A

they express CD40 and CD80/86

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84
Q

What is the clinical significance of CD21?

A

it is a B-cell marker and the receptor for EBV

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85
Q

What are superantigens?

A

bacterial antigens that cross-link the beta-region of the TCR to the MHC-II on APCs, causing a massive release of cytokines

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86
Q

What is the receptor for LPS that mediates toxic shock?

A

LPS binds CD14 (aka TLR4) on macrophages

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87
Q

What is CD14?

A

aka TLR4, it is an LPS receptor found on macrophages that mediates toxic shock

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88
Q

Name three viruses that are classic examples of antigenic variation.

A
  • HIV
  • Hib
  • HCV
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89
Q

What is passive immunity? Give examples of how it is acquired.

A

immunity conveyed by the receipt of preformed antibodies (e.g. IgA from breast milk, IgG via the placenta, antitoxin, humanized monoclonal antibodies)

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90
Q

After exposure to what five microbes are unvaccinated patients given preformed antibodies?

A

“To Be Healed Very Rapidly”

  • tetanus toxin
  • botulinum toxin
  • HBV
  • varicella
  • rabies virus
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91
Q

Which kind of vaccination is capable of inducing both a cellular and humoral response?

A

live attenuated vaccination

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92
Q

Which common vaccines are inactivated or killed vaccine?

A

“R.I.P. Always”

  • R: rabies
  • Influenza
  • Polio
  • Hep A
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93
Q

Which four common vaccines are live attenuated vaccines?

A

“May You Be Vivacious”

  • MMR
  • yellow fever
  • BCG
  • varicella
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94
Q

What defines acute and chronic inflammation?

A
  • acute: neutrophil infiltrate

- chronic: lymphocyte infiltrate

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95
Q

Acute inflammation arises in response to what two things?

A
  • infection

- tissue necrosis (neutrophils clear necrotic debris)

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96
Q

What is the downstream effect of activating a TLR?

A

up regulation of NF-kB, which leads to production of many more immune mediators

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97
Q

What is the role of arachidonic acid metabolites and how are they produced?

A
  • metabolites that mediate acute inflammation
  • AA is released from the cell membrane by phospholipase A2 and then acted upon by either COX or 5-lipoxygenase
  • COX produces prostaglandins while 5-lipoxygenase produces leukotrienes
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98
Q

How are prostaglandins produced?

A

AA is released from a cell membrane by phospholipase A2 and then acted upon by COX

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99
Q

How are leukotrienes produced?

A

AA is released from a cell membrane by phospholipase A2 and then acted upon by 5-lipoxygenase

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100
Q

What role do prostaglandins play in acute inflammation?

A

they mediate arteriolar vasodilation and increase vascular permeability in the post-capillary venule

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101
Q

What role do leukotrienes play in acute inflammation?

A

they are slow reacting substances of anaphylaxis and mediate vasoconstriction, bronchospasm, and increased vascular permeability (all things that involve smooth muscle contraction)

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102
Q

Describe the function of arachidonic acid metabolites.

A
  • they mediate acute inflammation
  • prostaglandins are produced by COX and mediate vasodilation of the arteriole as well as increase vascular permeability of the post-capillary venule
  • leukotrienes attract and activate neutrophils in addition to mediating vasoconstriction, bronchospasm, and increased vascular permeability
  • specifically, PGE2 also mediates pain and fever while LTB4 attracts and activates neutrophils
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103
Q

What are pericytes?

A

contractile cells that sit under endothelial cells in capillaries and post-capillary venules and open spaces to increase vascular permeability

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104
Q

What is the significance of PGE2 in acute inflammation?

A

it mediates pain and fever

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105
Q

What is the significance of LTB4 in acute inflammation?

A

it attracts and activates neutrophils

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106
Q

List three things that activate mast cells.

A
  • IgE cross-linking by antigen
  • C3a and C5a
  • tissue trauma
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107
Q

What are the fast and slow mediators of anaphylaxis?

A
  • fast: histamine, released from preformed granules

- slow: leukotrienes produced after mast cell activation

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108
Q

What is Hageman factor?

A
  • also known as FXII, it is a pro inflammatory protein produced by the liver, which activates coagulation and fibrinolytic systems, complement, and kinin systems
  • FXII defects cause hereditary angioedema because they activate kinin, which yields bradykinin
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109
Q

What is bradykinin and how is it produced?

A

kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which then mediates vasodilation, increased vascular permeability, and pain

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110
Q

What are the five cardinal signs of inflammation?

A
  • warmth
  • redness
  • pain
  • swelling
  • fever
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111
Q

What causes the warmth and redness of inflammation? What are the primary mediators of this mechanism?

A

arteriolar vasodilation mediated by histamine, prostaglandins, and bradykinin

112
Q

What causes the swelling associated with inflammation? What are the primary mediators of this mechanism?

A

leakage of fluid from post capillary venules mediated by histamine and tissue damage (endothelial disruption)

113
Q

What causes the pain associated with inflammation? What are the primary mediators of this mechanism?

A

PGE2 and bradykinin sensitize sensory nerve endings

114
Q

What mediates the fever associated with inflammation?

A

pyrogens trigger release of IL-1 and TNF by macrophages, which increase COX activity in perivascular cells of the hypothalamus where the internal temperature is regulated, increasing PGE2 and raising the set point

115
Q

List the primary mediators of each of the following in association with inflammation:

  • redness
  • warmth
  • swelling
  • pain
  • fever
A
  • redness: vasodilation - histamine, bradykinin, prostaglandins
  • warmth: vasodilation - histamine, bradykinin, prostaglandins
  • swelling: leakage of fluid from postcap venules - histamine and tissue damage
  • pain: sensitization - PGE2 and bradykinin
  • fever: pyrogens trigger IL-1 and TNF release, increasing PGE2 in the hypothalamus
116
Q

What are the 7 steps of neutrophil arrival and function during acute inflammation?

A
  • margination
  • rolling
  • adhesion
  • transmigration (aka diapedesis) and chemotaxis
  • phagocytosis
  • destruction of phagocytosed material
  • resolution
117
Q

What causes margination of neutrophils?

A

vasodilation slows blood flow in the post-capillary venules, causing cells to marginate from the center of flow

118
Q

What causes rolling of neutrophils?

A
  • endothelial cells up regulate selectins which bind sialyl Lewis X on leukocytes
  • P-selectins are released form Weibel-Palade bodies in response to histamine
  • E-selectins are induced by TNF and IL-1
119
Q

Weibel-Palade bodies contain what two things?

A
  • von Willebrand Factor for platelet adhesion

- P-selectins for neutrophil rolling

120
Q

What is sialyl Lewis X?

A

a selectin receptor expressed by leukocytes

121
Q

What role do selectins and integrins play in neutrophil recruitment to the site of inflammation?

A
  • selectins mediate rolling

- integrins mediate adhesion

122
Q

Describe the process of neutrophil adhesion.

A
  • TNF and IL-1 up regulate cellular adhesion molecules on endothelial cells (e.g. ICAM)
  • C5a and LTB4 up regulate integrin expression on leukocytes, specifically CD11/18 known as LFA-1 and Mac-1
  • the interaction results in firm adhesion to the vessel wall
123
Q

What role do C5a and LTB4 play in neutrophil recruitment?

A

they induce expression of integrins important for neutrophil adhesion to endothelial walls

124
Q

Neutrophils are attracted by what four things?

A
  • bacterial products
  • C5a
  • IL-8
  • LTB4
125
Q

Describe the enzymatic steps of O2-dependent killing of phagocytosed microbes.

A
  • NADPH oxidase converts O2 to superoxide (O2.-)
  • superoxide dismutase converts superoxide to hydrogen peroxide
  • myeloperoxidase converts hydrogen peroxide to bleach (HOCl)
126
Q

What are the two mechanisms of O2-independent killing of phagocytosed microbes?

A

uses enzymes present in secondary granules

  • lysozyme in macrophages
  • major basic protein in eosinophils
127
Q

Neutrophils undergo apoptosis and disappear within what period following resolution of the inflammatory stimulus?

128
Q

While neutrophils utilize O2-dependent killing of phagocytosed microbes, macrophages rely more on what?

A

O2-independent killing in the form of lysozyme released from secondary granules

129
Q

Macrophages predominate at what point during the course of inflammation?

A

after neutrophils, about 2-3 days after inflammation begins

130
Q

What is the role of macrophages in acute inflammation?

A

arrive after neutrophils and manage the next step of the inflammatory process whether that be resolution, abscess formation, chronic inflammation, etc.

131
Q

How do macrophages induce resolution and healing, continued acute inflammation, abscess formation, or chronic inflammation depending on the situation?

A
  • resolution: secrete anti-inflammatory IL-10 and TGF-B
  • continue acute: secrete IL-8 to recruit more neutrophils
  • abscess: secrete fibrogenic growth factors and cytokines
  • chronic inflammation: activate CD4 helper T cells
132
Q

What induces the Th1 phenotype and what is the role of these helper T cells? What do they secrete to do so?

A
  • induced by IL-12 and IFNy
  • they promote cytotoxic T cell functioning
  • by secreting IL-2 as a CD8 activator and growth factor
  • and by secreting IFNy to activate macrophages and inhibit the Th2 phenotype
133
Q

What induces the Th2 phenotype and what is the role of these helper T cells? What do they secrete to do so?

A
  • induced by IL-4
  • they promote B cell functioning and a humoral response
  • secrete IL-4 to promote IgE class switching
  • secrete IL-5 to promote IgA class switching
  • secrete IL-10 to inhibit the Th1 phenotype
134
Q

CD8 T cells kill via what two mechanisms?

A
  • perforin/granzyme

- Fas/FasL

135
Q

CD8 cells require what two signals to become activated?

A
  • bind MHC-I

- bind IL-2

136
Q

What is the defining feature of granulomatous inflammation?

A

the presence of epithelioid histiocytes

137
Q

Describe the histology of a classic granuloma.

A

a collection of epithelioid histiocytes and giant cells surrounded by a rim of lymphocytes

138
Q

How do non-caseating and caseating granulomas differ in their appearance and in their causes?

A
  • non-caseating lack central necrosis and are caused by a reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease
  • caseating have central necrosis and are characteristic of TB and fungal infection
139
Q

How can you differentiate a TB caseating granuloma from a fungal caseating granuloma?

A
  • TB stains AFB positive

- fungal stains GMS positive

140
Q

Describe how granulomas form.

A
  • macrophages become activated and secrete IL-12, which induces Th1 differentiation
  • Th1 cells then secrete IFNy, which converts macrophages to epithelioid histiocytes
  • macrophages secrete TNFa which induces and maintains granuloma formation
141
Q

What is autoimmune lymphoproliferative syndrome? How does it present?

A
  • mutations in the Fas apoptosis pathway impair peripheral tolerance mechanisms for T and B cells such that they self-reactive lymphocytes proliferate
  • it presents with symptoms of autoimmune dysfunction as well as lymphadenopathy and an increased risk of lymphoma
142
Q

Describe the negative selection of T cells. Where does it occur? What other cells are involved? What is being tested?

A
  • negative selection takes place in the medulla
  • dendritic cells express self antigens and medullary epithelial cells express peripheral antigens
  • cells that have an affinity for self-antigens undergo apoptosis
143
Q

Describe B cell negative selection. Where does it occur? What is being tested? What happens when cells fail?

A
  • it takes place in the bone marrow
  • B cells are tested for recognition of self-antigens
  • if they do bind self-antigens, they undergo either receptor editing or apoptosis
144
Q

What is B cell receptor editing? What genes must be re-expressed? What portion of the BCR undergoes further recombination?

A
  • a process B cells can undergo rather than apoptosis if they fail negative selection
  • the cell re-expresses the RAG genes
  • the light chain undergoes recombination again
145
Q

What is IPEX syndrome? What causes it? How does it present?

A
  • results from a FOXP3 mutation that causes dysfunction of regulatory T cells
  • IPEX stands for immune dysregulation, polyendocrinopathy (thyroiditis or type I DM), enteropathy, X-linked
146
Q

Why is it believed that women of childbearing age are most affected by autoimmune disorders?

A

because estrogen may reduce apoptosis of self-reactive B cells

147
Q

CD25 and FOXP3 polymorphisms result in what conditions?

A
  • both are important for regulatory T cell functioning
  • CD25 polymorphisms are associated with Type I DM and MS
  • FOXP3 polymophisms are associated with IPEX syndrome
148
Q

Describe peripheral tolerance. How is it mediated?

A
  • occurs when T cells bind an antigen via the TCR, but this event doesn’t coincide with the second activation signal of B7/CD28 binding
  • repeated instances of this triggers expression of FasL by the T cell
  • FasL then binds Fas and induces apoptosis of the T cell and other nearby, self-reactive T cells
149
Q

What is PTPN22?

A
  • a tyrosine phosphatase that affects B and T cell receptor signaling
  • polymorphisms can lead to a gain of function with inhibits the signaling needed for peripheral tolerance and anergy, increasing the risk of autoimmunity
150
Q

What is bystander activation?

A

incidental activation of a self-reactive lymphocyte by cytokines released in response to a genuine microbe (infection leads to release of cytokines and up-regulation of the necessary activation signals, allowing a self-reactive lymphocyte to leave a state of anergy)

151
Q

Describe the pathogenesis of SLE.

A
  • UV damage to keratinocytes causes apoptosis
  • the apoptotic debris isn’t cleared effectively and it activates self-reactive lymphocytes
  • these lymphocytes then produce antibodies to host nuclear antigens
  • antigen-antibody complexes are generated at low levels and taken up by dendritic cells
  • these DNA antigens activate TLRs in dendritic cells, amplifying the immune response
  • higher levels of antigen-antibody complexes are generated and deposited into multiple tissues
  • complement is activated, causing tissue damage
152
Q

What is CH50?

A

a test of complement function that measures complements ability to lyse RBCs

153
Q

What are the classic findings of SLE.

A
  • non-specific: fever, weight loss, Raynaud phenomenon
  • malar or discoid rash, especially upon exposure to sunlight
  • painless nasopharyngeal ulcers
  • arthritis
  • serositis
  • psychosis
  • renal damage (diffuse proliferative glomerulonephritis is the most common nephritic syndrome, membranous glomerulonephritis the most common nephrotic syndrome)
  • anemia, thrombocytopenia
  • Libman-Sacks endocarditis (small vegetations on both sides of the mitral valve)
  • ANA (sensitive but not specific)
  • anti-dsDNA (specific, indicates poor prognosis) or anti-Sm antibodies (specific, not an indicator of prognosis)
154
Q

Name a very sensitive antibody found in SLE patients? What about a very specific one?

A
  • ANA is very sensitive

- anti-dsDNA or anti-Sm antibodies are very specific

155
Q

What is Libman-Sacks endocarditis?

A

a form of endocarditis characteristic of SLE in which vegetations are found on both sides of the mitral valve

156
Q

What is an anti-phospholipid antibody? Give three examples.

A
  • an autoantibody direct against proteins bound to phospholipids
  • anti-cardiolipin, anti-B2-glycoprotein I, and lupus anticoagulant are all examples
157
Q

Anti-cardiolipin anti-phospholipid antibodies can cause what clinical confusion?

A

they can produce a false-positive syphilis test

158
Q

Antiphospholipid Antibody Syndrome

A
  • a hypercoagulable state due to antiphospholipid antibodies, primarily lupus anticoagulant
  • associated with SLE but more often a primary disorder
  • results in arterial and venous thrombosis, recurrent pregnancy loss, and cerebral thrombosis (stroke)
  • treat with lifelong systemic anticoagulation
159
Q

Drug-Induced Lupus

A
  • it is a drug-induced form of SLE defined by antihistone antibodies
  • procainamide, hydrazine, and isoniazid are common causes
  • presents like SLE but CNS and renal involvement are rare, removal of the drug usually results in remission
160
Q

Mortality due to SLE is usually the result of what complications?

A
  • renal failure
  • infection (from immunosuppression and complement depletion)
  • accelerated coronary atherosclerosis
161
Q

What is the most common renal complication in someone with SLE?

A

diffuse proliferative glomerulonephritis

162
Q

Sjogren Syndrome

A
  • a type IV HSR and autoimmune destruction of lacrimal and salivary glands with fibrosis
  • presents with dry eyes, dry mouth, recurrent dental carries and complaints of “can’t chew a cracker” or “dirt in my eyes”
  • may progress to ulceration of corneal epithelium
  • unilateral enlargement of the parotid gland often occurs late and carries a risk for B-cell lymphoma (marginal zone)
  • can be primary or associated with another AI disorder, especially RA
  • characterized by ANA and anti-ribonucleoprotein antibodies (anti-SSA and anti-SSB)
  • SSA and SSB are associated with extra glandular manifestations and SSA poses a risk for delivering babies with neonatal lupus and congenital heart block
  • lymphocytic sialadenitis on lip biopsy is very specific
163
Q

What is SSA? What diseases is it associated with? What risk does it pose?

A
  • a self-reactive anti-ribonucleoprotein antibody that is seen in Sjogrens and SLE
  • it can cross the placenta and cause neonatal lupus or congenital heart block
  • therefore, screen pregnant SLE and Sjogrens patients
164
Q

Scleroderma

A
  • an autoimmune disorder characterized by sclerosis of the skin and visceral organs
  • autoimmune damage to mesenchyme triggers endothelial dysfunction, which leads to inflammation, vasoconstriction, and secretion of fibroblast growth factors (TGF-B and PDGF)
  • fibrosis is initially perivascular but extends to cause organ damage with time
  • limited type: skin involvement is limited to the hands and face with late visceral involvement; CREST syndrome is the prototype
  • diffuse type: skin involvement is diffuse with early visceral involvement; can involve any organ but most often presents with esophageal dysmotility and reflux, interstitial fibrosis and pulmonary hypertension, or sclerodermal renal crisis
  • highly associated with antibodies to DNA topoisomerase I also known as anti-Scl-70
165
Q

What is CREST syndrome? What are the features?

A
  • the prototype limited scleroderma
  • CREST: Calcinosis/anti-Centromere antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias of the skin
166
Q

What is mixed connective tissue disease?

A

an auto-immune disease with mixed features of SLE, diffuse scleroderma, and polymyositis characterized by ANA and serum antibodies to U1 ribonucleoprotein

167
Q

Tissues can be divided into what three types based on their regenerative capacity?

A
  • labile (stems cells continuously cycle)
  • stable (cells are quiescent but can reenter the cell cycle)
  • permanent (permanent lack of regenerative potential)
168
Q

What is a classic example of tissue with stable regenerative potential?

A

regeneration of the liver by compensatory hyperplasia after partial resection as each hepatocyte produces additional cells

169
Q

What kind of wound healing follows MI?

A

repair (not regeneration)

170
Q

Describe the process of wound healing by repair.

A
  • granulation tissue forms first, consisting of fibroblasts, capillaries, myofibroblasts, and type III collagen
  • type III collagen is replaced with type I by collagenase
171
Q

What is granulation tissue and what is it composed of?

A
  • it is the first phase of wound healing by repair

- formed by fibroblasts laying down type III collagen, myofibroblasts, and dense capillaries

172
Q

What is collagenase? What cofactor does it require?

A

an enzyme that removes type III collagen in granulation tissue and replaces it with type I, requiring zinc

173
Q

What are the four types of collagen used for?

A
  • type 1: bone, skin, tendon, dentin, fascia, cornea, late wound repair
  • type 2: car”two”lage, vitreous body, nucleus pulposus
  • type 3: granulation tissue, uterus, embryonic tissue, keloids (flexible), blood vessels
  • type 4: basement membranes, basal lamina, lens
174
Q

List the function of each of the following growth factors in wound healing:

  • TGF-a
  • TGF-B
  • platelet derived growth factor
  • fibroblast growth factor
  • vascular endothelial growth factor
  • epidermal growth factor
A
  • TGF-a: epithelial and fibroblast growth factor
  • TGF-B: fibroblast growth factor, cell cycle arrest
  • PDGF: growth factor for endothelium, smooth muscle, and fibroblasts
  • FGF: important for angiogenesis
  • VEGF: important for angiogenesis
  • EGF: stimulates cell growth via TKs
175
Q

What are healing by primary and secondary intention?

A
  • primary: wound edges are brought together
  • secondary: edges are not approximated, granulation tissue fills the defect, myofibroblasts contract the wound, forming a scar
176
Q

Granulation tissue forms in what type of healing, that by primary or secondary intention?

A

secondary intention only

177
Q

Name five causes of delayed wound healing.

A
  • infection is the most common
  • vitamin C, copper, or zinc deficiency
  • foreign body
  • ischemia
  • diabetes
178
Q

Why do vitamin C, copper, and zinc deficiencies all impair wound healing?

A
  • vitamin C is important in the hydroxylation of proline and lysine pro collagen residues, which are later needed for cross-linking
  • copper is a cofactor for lysol oxidase, which cross links lysine and hydroylysine to form stable collagen
  • zinc is a cofactor for collagenase, which replaces type III collagen
179
Q

What is the difference between a hypertrophic scar and a keloid?

A
  • hypertrophic: excess production is localized to the wound and formed by excess type I collagen and there is the possibility for spontaneous remission
  • keloids are composed of excess, disorganized type III collagen and are out of proportion to the wound; they are likely to regrow if removed
180
Q

Where are keloids classically found?

A

on the ear lobs of African Americans

181
Q

Type I hypersensitivities are mediated by what?

A

IgE on presensitized mast cells and basophils

182
Q

Atopic disorders like rhinitis and hay fever are what kind of hypersensitivity reaction?

183
Q

Describe the mechanism behind type II hypersensitivity reactions.

A

IgM or IgG bind to fixed antigens on “enemy” cells and trigger cytotoxic events (phagocytosis, complement fixation, or antibody-mediated cellular dysfunction)

184
Q

What is the difference between a direct and an indirect Coombs test?

A
  • direct: detects antibodies that have adhered to patient’s RBCs
  • indirect: detects antibodies in serum that can adhere to other RBCs
185
Q

Describe the mechanism of type III hypersensitivity reactions.

A
  • IgG-antigen complexes activate complement, which attracts neutrophils
  • these neutrophils release lysosomal enzymes, causing tissue damage
186
Q

Serum Sickness

A
  • a type III hypersensitivity in which antibodies to foreign proteins are produced
  • most cases caused by drugs acting as haptens
  • presents with fever, urticaria, arthralgia, proteinuria, and lymphadenopathy 5-10 days after antigen exposure
187
Q

Arthus Reaction

A
  • a local, subacute type III hypersensitivity
  • caused by injection of antigen into a presensitized individual (IgG already formed)
  • manifests with edema, necrosis, and activation of complement
188
Q

How does serum sickness compare to an arthus reaction?

A
  • both are type III hypersensitivities mediated by IgG
  • however, an arthus reaction has a more rapid onset because it is mediated by circulating IgG (the individual has already been sensitized)
  • an arthus reaction is more localized than serum sickness
189
Q

Name the three major diseases that are type IV hypersensitivities.

A

The 3 T’s

  • TB
  • Transplant rejection
  • Touching (contact dermatitis)
190
Q

Allergic Transfusion Reaction

A
  • a reaction to transfused plasma proteins (so risk is plasma>SDP>pooled platelets>RBCs)
  • presents with urticaria, local erythema, pruritis, fever, and wheezing
  • treat with antihistamines and restart the transfusion slowly
191
Q

Anaphylactic Transfusion Reaction

A
  • usually a reaction of IgA-deficient patients to blood products containing IgA
  • presents with dyspnea, shock, and respiratory arrest
  • treat with epinephrine
192
Q

Febrile, Nonhemolytic Transfusion Reaction

A
  • a type II hypersensitivity reaction of host antibodies against donor HLA antigens/WBCs and the presence of cytokines in the product
  • presents with fever, chills, and flushing
  • prevent with leukoreduction
  • treat with tylenol
193
Q

Acute Hemolytic Transfusion Reaction

A
  • a type II hypersensitivity due to ABO incompatibility
  • causes an intravascular hemolysis
  • presents with fever, hypotension, tachypnea, tachycardia, and hemoglobinuria
194
Q

List the disorder(s) associated with each of the following antibodies:

  • anti-ACh receptor
  • anti-basement membrane
  • anticardiolipin or lupus anticoagulant
  • anticentromere
  • anti-desmoglein
  • anti-hemidesmosome
  • anti-dsDNA or anti-Sm
A
  • ACh receptor: myasthenia gravis
  • BM: good pasture syndrome
  • cardiolipin or lupus anticoagulant: SLE or anti phospholipid syndrome
  • centromere: limited scleroderma (CREST)
  • desmoglein: pemphigus vulgaris
  • hermidesmosome: bullies pemphigoid
  • dsDNA/Sm: SLE
195
Q

List the disorder(s) associated with each of the following antibodies:

  • anti-glutamic acid decarboxylase (GAD-65)
  • anti-histone
  • anti-jo-1, anti-SRP, or anti-Mi-2
  • anti-microsomal or anti-thyroglobulin
  • anti-mitochondrial
  • anti-nuclear
  • anti-parietal cell
A
  • GAD65: type 1 DM
  • histone: drug-induced lupus
  • jo-1, SRP, Mi-2: polymyositis and dermatomyositis
  • microsomal, thyroglobulin: Hashimoto thyroiditis
  • mitochondrial: primary biliary cirrhosis
  • ANA: SLE, nonspecific
  • parietal cell: pernicious anemia
196
Q

List the disorder(s) associated with each of the following antibodies:

  • anti-phospholipase A2 receptor
  • anti-Scl-70 (aka anti-DNA topoisomerase I)
  • anti-smooth muscle
  • anti-SSA, anti-SSB
  • anti-TSH receptor
  • anti- U1 RNP (ribonucleoprotein)
A
  • phospholipase A2 receptor: primary membranous nephropathy
  • topoisomerase I: diffuse scleroderma
  • smooth muscle: autoimmune hepatitis type I
  • SSA/SSB: sjogren syndrome
  • TSH receptor: Graves
  • U1 RNP: mixed connective tissue disease
197
Q

Celiac disease is characterized by the presence of which autoantibodies?

A

anti-endomysial or anti-tissue transglutaminase IgA

198
Q

Rheumatoid arthritis is characterized by the presence of which autoantibodies?

A
  • rheumatoid factor (IgM against the Fc region of IgG)

- anti-CCP

199
Q

X-linked Agammaglobulinemia

A
  • an X-linked BTK mutation prevents B cell maturation
  • presents with bacterial and enteroviral infections after 6 months of age
  • see diminished levels of all Ig isotopes and scant/absent lymph nodes and tonsils
200
Q

Selective IgA Deficiency

A
  • unknown mechanism
  • typically asymptomatic but with increased risk of airway and GI infections, autoimmune disease, and atopy
  • decreased IgA but normal levels of other isotypes
201
Q

What is the most common primary immunodeficiency?

A

selective IgA deficiency

202
Q

Common Variable Immune Deficiency

A
  • B cell or helper T cell defects impair B-cell differentiation
  • often acquired in the 20s-30s with increased risk of autoimmune disease, bronchiectasis, lymphoma, and sinopulmonary infections
  • you can observe a decrease in plasma cells and all Ig isotypes
203
Q

DiGeorge Syndrome

A
  • 22q11 deletion causes failure of the 3rd and 4th pharyngeal pouches to develop, leaving the thymus and parathyroids absent
  • presents with cardiac anomalies, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia
  • measurable reduction in T cells, PTH, and calcium as well as an absent thymic shadow on CXR
204
Q

IL-12 Receptor Deficiency

A
  • loss of the receptor diminishes the Th1 response in an autosomal recessive manner
  • presents with disseminated mycobacterial and fungal infections, often after administering the BCG vaccine
  • measurable decrease in IFNy
205
Q

Hyper-IgE Syndrome

A
  • an autosomal dominant STAT3 mutation impairs ability of Th17 cells to recruit neutrophils
  • manifests with the “FATED” syndrome of coarse Facies, staph Abscesses, retained primary Teeth, increased IgE, and Dermatologic problems (eczema)
206
Q

Describe the defect that leads to chronic mucocutaneous candidiasis.

A

T-cell dysfunction results in noninvasive candida infections of the skin and mucous membranes

207
Q

Severe Combined Immune Deficiency

A
  • can be X-linked due to an IL-2R gamma chain mutation
  • or autosomal recessive due to an adenosine deaminase deficiency which allows the build up of amines toxic to lymphocytes
  • presents with failure to thrive, chronic diarrhea, thrush, and recurrent infections (“bubble baby”)
  • can find diminished TRECs and there is an absence of thymic shadow, germinal centers, and T cells
208
Q

Name two immunodeficiencies that present with an absent thymic shadow on CXR.

A
  • SCID

- DiGeorge syndrome

209
Q

What is a “sail sign”?

A

a normal feature of a child’s CXR which is also known as the thymic shadow, absent in those with DiGeorge syndrome or SCID

210
Q

Ataxia-Telangiectasia

A
  • ATM gene mutations result in the inability to repair DNA double strand breaks
  • presents with a triad of cerebellar defects (ataxia), spider angiomas, and IgA deficiency (the three A’s)
  • AFP is elevated in serum; IgA, IgG, and IgE are all reduced; and there is lymphopenia as well as cerebellar atrophy
211
Q

Hyper-IgM Syndrome

A
  • an X-linked recessive CD40L defect in Th cells impairs class switching
  • presents with opportunistic infections
  • IgM is elevated while all other Ig isotypes are absent
212
Q

Wiskott-Aldrich syndrome

A
  • an X-linked recessive mutation in the WAS gene impairs actin reorganization
  • presents with “WATER”: Wiskott Aldrich, thrombocytopenia, eczema, and recurrent infections
  • bleeding is a major cause of death
213
Q

Leukocyte Adhesion Deficiency Type 1

A
  • autosomal recessive defect in LFA-1 integrin (CD18) impairs extravasation of phagocytes
  • presents with recurrent skin and mucosal infections without pus formation, impaired wound healing, and delayed separation of umbilical cord
  • neutrophil count is elevated because they can’t leave circulation
214
Q

Chediak-Higashi Syndrome

A
  • autosomal recessive defect in the lysosomal trafficking regulator LYST which results in a microtubule defect that impairs fusion of phagosomes with lysosomes
  • increases one’s risk for pyogenic infections by Staph and Strep
  • presents with pancytopenia because the microtubule defect impairs mitosis and leads to intramedullary death
  • giant granules in leukocytes because they can’t be distributed and accumulate at the golgi instead
  • presents with defective primary hemostasis due to abnormal dense granules in platelets
  • albinism because melanocytes can’t hand off pigment to keratinocytes
  • peripheral neuropathy because axonal and dendritic transport are impaired
215
Q

Chronic Granulomatous Disease

A
  • X-linked recessive NADPH oxidase deficiency limits oxidative burst in neutrophils
  • increased susceptibility to catalase positive organisms (especially Pseudomonas cepacia, serrate, nocardia, and aspergillus)
  • abnormal dihydrorhodamine test and no reaction to nitro blue tetrazolium dye
216
Q

Those with chronic granulomatous disease are more susceptible to which organisms?

A

reduced oxidative burst leaves them more susceptible to catalase + organisms (Cats Need PLACESS to Belch their Hairballs):

  • Cat = catalase positive
  • Nocardia
  • Pseudomonas cepacia
  • Listeria
  • Aspergillus
  • Candida
  • E. Coli
  • Staph
  • Serratia
  • B cepacia
  • H pylori
217
Q

What is an myeloperoxidase deficiency? How can you distinguish it from chronic granulomatous disease?

A
  • it is an MPO deficiency that prevents conversion of hydrogen peroxide to bleach for O2-dependent killing of phagocytosed microbes
  • nitro blue tetrazolium test is normal unlike CGD
218
Q

B-cell deficiencies tend to leave one more susceptible to what kinds of infections? What about T-cell deficiencies?

A
  • B cell deficiencies produce recurrent bacterial infections

- T cell deficiencies produce more fungal and viral infections

219
Q

T cell deficiencies leave one more susceptible to which bacterial, viral, and fungal infections?

A
  • bacterial sepsis
  • CMV, EBV, JCV, VZV, and chronic respiratory/GI viruses
  • local candida
220
Q

B cell deficiencies leave one more susceptible to which bacterial, viral, and fungal infections?

A
  • encapsulated bacteria (Please SHINE my SKiS): P. aeruginosa, Strepneumoniae, Hib, N. meningitidis, E. coli, Salmonella spp., K. pneumoniae, Group B Strep
  • enteroviral encephalitis and poliovirus
  • GI giardiasis (due to lack of IgA)
221
Q

Granulocyte deficiencies leave one more susceptible to which bacterial, viral, and fungal infections?

A
  • Staph, B cepacia, P. aeruginosa, Serratia, Nocardia

- systemic candida, aspergillus

222
Q

Complement deficiencies leave one more susceptible to which infections?

A
  • early component deficiencies leave one susceptible to encapsulated bacteria (Please SHiNE my SKiS
  • late component (MAC) deficiencies leave one susceptible to Neisseria
223
Q

What mediates hyperacute, acute, and chronic transplant rejection? What type of hypersensitivity is each?

A
  • hyperacute: pre-existing recipient antibodies to donor antigen activate complement (type II hypersensitivity)
  • acute: CD8 T cells against donor MHC (type IV) and antibodies to donor antigens formed after transplant
  • chronic: CD4 T cells against recipient APCs presenting donor peptides (type II and IV)
224
Q

Hyperacute Transplant Rejection

A
  • pre-existing recipient antibodies react to donor antigens and activate complement
  • causing widespread thrombosis of graft vessels, ischemia, and necrosis
  • must remove the grafted organ
225
Q

Acute Transplant Rejection

A
  • CD8 T cells attack donor MHCs in addition to antibodies forming after transplant to graft antigens
  • causes a vasculitis of graft vessels
  • can be prevented or reversed with immunosuppressants
226
Q

Chronic Transplant Rejection

A
  • CD4 T cells respond to recipient APCs presenting donor peptides, triggering a cellular and humoral response (type II and IV hypersensitivity)
  • cytokine response causes atrophy of the graft, interstitial fibrosis, and arteriosclerosis
227
Q

Describe the mechanism and presentation of GvHD. What kind of transplants are most plagued by GvHD?

A
  • grafted immunocompetent T cells proliferate and reject host cells
  • causes maculopapular rash, jaundice, diarrhea, and hepatosplenomegaly
  • most often in HSCT or liver transplants because these are rich in lymphocytes
228
Q

Which drugs pose a risk of granuloma break down and disseminated disease?

A

TNFa inhibitors

229
Q

Why are granulomas associated with hypercalcemia?

A

they produce calcitriol

230
Q

which bacterial, fungal, and parasitic organisms are likely to cause granulomas to form?

A
  • bacteria: Mycobacteria (TB and leprosy), B. henselae (cat scratch), Listeria, Treponema pallidum (tertiary syphilis)
  • fungal: endemic mycoses
  • parasites: schistosomiasis
231
Q

Which anti-inflammatory conditions cause granulomas to form?

A
  • sarcoidosis
  • Crohn disease
  • primary biliary cirrhosis
  • subacute thryoiditis
  • granulomatosis with polyangiitis
  • eosinophilic granulomatosis
  • giant cell arteritis
  • Takayasu arteritis
232
Q

What is the difference between a transudate and exudate?

A
  • exudates are thicker: they are cellular with high protein and LDH content as well as a higher specific gravity
  • transudates are hypo cellular with low specific gravity, protein, and LDH
233
Q

What are the primary causes of transudates and exudates?

A
  • transudates: increased hydrostatic pressure or decreased oncotic pressure (due to cirrhosis or a nephrotic syndrome)
  • exudate: lymphatic obstruction, inflammation, or malignancy
234
Q

What is ESR a measure of? What causes it to vary?

A
  • a measure of inflammation
  • products of inflammation (mainly fibrinogen) coat RBCs and cause aggregation, and during the test, denser RBC aggregates fall faster which elevates the ESR
235
Q

What would cause an elevated or depressed ESR?

A
  • elevated: most anemias, infections, inflammation, cancer, renal disease, and pregnancy
  • depressed: sickle cell anemia (altered shape), polycythemia (increased RBCs dilute aggregation factors), HF, microcytosis, hypofibrinogenemia
236
Q

How is SLE treated?

A
  • NSAIDs
  • steroids
  • immunosuppressants
  • hydroxychloroquine
237
Q

What role do anti-dsDNA, ANA, anti-Sm, and antihistone antibodies play in SLE?

A
  • ANA is a sensitive, but non-specific, marker
  • anti-dsDNA are specific and indicative of a poor prognosis
  • anti-Sm are specific but don’t have any prognostic significance
  • antihistone antibodies are sensitive for drug-induced lupus
238
Q

What are anti-Smith antibodies?

A

specific markers for SLE that are directed against snRNPs

239
Q

What is the purpose of down-regulating albumin as an acute phase reactant?

A

reduced production conserves amino acids for positive reactants

240
Q

What are the functions of IL-2?

A

stimulate growth of helper, cytotoxic, and regulatory T cells as well as NK cells

241
Q

What are the functions of IL-4?

A
  • induces the Th2 phenotype
  • promotes growth of B cells
  • enhances class switching to IgE and IgG
242
Q

What are the functions of IL-5?

A
  • promotes growth and differentiation of B cells with IgA class switching
  • stimulates growth and differentiation of eosinophils
243
Q

Cyclosporine (mechanism, use, toxicity)

A
  • blocks T cell activation by binding cyclophilin and inhibiting calcineurin, which causes less NFAT to be produced (a transcription factor for IL-2)
  • used for transplant rejection prophylaxis, psoriasis, and RA
  • highly nephrotoxic; may also cause HTN, hyperlipidemia, hirsutism, and gingival hyperplasia
244
Q

Tacrolimus (mechanism, use, toxicity)

A
  • blocks T cell activation by binding FK506 binding protein and inhibiting calcineurin, which causes less NFAT to be produced (a transcription factor for IL-2)
  • used for transplant rejection prophylaxis
  • highly nephrotoxic with increased risk for diabetes and neurotoxicity
245
Q

Sirolimus

A
  • blocks T cell activation and B cell differentiation by preventing a response to IL-2
  • it does this by binding FK506 binding protein and inhibiting mTOR, a part of the IL-2R signal cascade
  • used for kidney transplant rejection prophylaxis
  • causes pancytopenia, insulin resistance, and hyperlipidemia but is not nephrotoxic
246
Q

Daclizumab

A
  • a monoclonal antibody that blocks IL-2R
  • used for kidney transplant rejection prophylaxis
  • may cause edema, hypertension, tremor
247
Q

Basiliximab

A
  • a monoclonal antibody that blocks IL-2R
  • used for kidney transplant rejection prophylaxis
  • may cause edema, hypertension, tremor
248
Q

Azathioprine

A
  • an antimetabolite precursor of 6-MP, which inhibits PRPP amidotransferase and thus purine synthesis
  • used for transplant rejection prophylaxis, RA, Crohn disease, and other autoimmune conditions
  • may cause leukopenia, anemia, or thrombocytopenia
  • toxicity is enhanced by allopurinol because 6-MP is degraded by xanthine oxidase as well
249
Q

Mycophenolate Mofetil

A
  • a drug that reversibly inhibits IMP dehydrogenase to prevent purine synthesis in B and T cells
  • used for transplant rejection prophylaxis and lupus nephritis
  • may cause GI upset or pancytopenia and is associated with invasive CMV infection
250
Q

What is aldesleukin and how is it used clinically?

A
  • it is recombinant IL-2

- used for renal cell carcinoma and metastatic melanoma

251
Q

What is epoetin alfa and how is it used clinically?

A
  • it is recombinant EPO

- used to treat anemias in those with renal failure

252
Q

What is filgrastim and how is it used clinically?

A

it is recombinant G-CSF used to promote the recovery of bone marrow

253
Q

What is sargramostim and how is it used clinically?

A

it is recombinant GM-CSF used to promote the recovery of bone marrow

254
Q

How do we used IFN-a clinically?

A

to treat chronic HBV and HCV as well as Kaposi sarcoma and malignant melanoma

255
Q

How do we use IFN-B clinically?

A

for the treatment of MS

256
Q

How do we used IFN-y clinically?

A

for the treatment of chronic granulomatous disease

257
Q

What is oprelvekin and how is it used clinically?

A

it is recombinant IL-11 used to treat thrombocytopenia

258
Q

What is romiplostim and how is it used clinically?

A

a recombinant thrombopoietin receptor agonist used to treat thrombocytopenia

259
Q

What is eltrombopag and how is it used clinically?

A

a recombinant thrombopoietin receptor agonist used to treat thrombocytopenia

260
Q

What is the target of alemtuzumab and how do we used it clinically?

A

targets CD52 for the treatment of CLL and MS

261
Q

What is the target of bevacizumab and how do we used it clinically?

A

targets VEGF for the treatment of colorectal cancer, renal cell carcinoma, and neovascular age-related macular degeneration

262
Q

What is the target of cetuximab and how do we used it clinically?

A

targets EGFR for the treatment of colorectal, head, and neck cancer

263
Q

What is the target of rituximab and how do we used it clinically?

A

targets CD20 to treat non-Hodgkin lymphoma, CLL, RA, and ITP

264
Q

What is the target of trastuzumab and how do we used it clinically?

A

targets HER2/neu for the treatment of breast cancer

265
Q

What is the target of adalimumab and how do we used it clinically?

A

targets TNF-a for the treatment of IBD, RA, ankylosing spondylitis, and psoriasis

266
Q

What is the target of certolizumab and how do we used it clinically?

A

targets TNF-a for the treatment of IBD, RA, ankylosing spondylitis, and psoriasis

267
Q

What is the target of infliximab and how do we used it clinically?

A

targets TNF-a for the treatment of IBD, RA, ankylosing spondylitis, and psoriasis

268
Q

What is entercept and how do we used it clinically?

A

a decoy TNF-a receptor used to treat IBD, RA, ankylosing spondylitis, and psoriasis

269
Q

What is the target of eculizumab and how do we used it clinically?

A

targets C5 for the treatment of paroxysmal nocturnal hemoglobinuria

270
Q

What is the target of natalizumab and how do we used it clinically?

A

targets a4-integrin for the treatment of MS and Crohn disease

271
Q

What is the target of abciximab and how do we used it clinically?

A

targets platelet glycoproteins GP IIb-IIIa to prevent ischemic complications in patients undergoing percutaneous coronary intervention

272
Q

What is the target of denosumab and how do we used it clinically?

A

targets RANKL in those with osteoporosis to inhibit osteoclast maturation

273
Q

What is the target of omalizumab and how do we used it clinically?

A

targets IgE to treat those with allergic asthma

274
Q

What is the target of palivizumab and how do we used it clinically?

A

targets the RSV F protein to prevent RSV infection in high-risk infants

275
Q

What is the target of ranibizumab and how do we used it clinically?

A

targets VEGF for the treatment of neovascular age-related macular degeneration

STEP1 (24 decks)

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