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Block 2 > Immunodeficiencies & Immunosuppressants > Flashcards

Immunodeficiencies & Immunosuppressants Flashcards

1
Q

Asthma

A
  • eosinophils = major leukocyte that infiltrates the lungs
  • Th2 cells produce IL-5 and IL-13 ==> eosinophil production in bone marrow, attract to lungs
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2
Q

Congenital (primary) vs acquired (secondary) immunodeficiencies

A

Congenital:
- Recurrent and overwhelming infections in young children
- Infections reflect the component of the immune system that is impaired

Acquired:
- Malnutrition, HIV, cytotoxic drugs, immunosuppressive drugs, cancers of bone marrow

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3
Q

B-cell immunodeficiency clinical manifestations

A

B-cell deficiencies:
- Pyogenic, encapsulated bacterial infections
- increased infections of the upper respiratory, GI, and urinary tracts
- Bacteria: Strep pneumo, H flu, Neisseria meningitidis, Staph aureus, Pseudomonas
- Viruses: enteroviruses, rotavirus
- Protozoa: giardia, cryptosporidium

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4
Q

T cell immunodeficiency clinical manifestations

A

T-cell deficiencies:
- severe viral infections
- severe fungal infections (Pneumocystis jiroveci), opportunistic infections
- virus-associated malignancies (EBV-associated lymphomas)
- chronic infectious diarrhea
- failure to thrive

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5
Q

Phagocyte immunodeficiency clinical manifestations

A

Phagocytes:
- skin abscess pneumonia lymphadenitis
- infection with catalase-positive organisms (Chronic Granulomatous Disease)
- delayed umbilical cord separation (Leukocyte Adhesion Deficiency)

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6
Q

Complement deficiency clinical manifestations

A

Complement:
- infections with encapsulated bacteria
- Lupus - early development
- recurrent neisserial infections

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7
Q

NK cell deficiency clinical manifestations

A

NK cells:
- Herpesvirus infections
- increased malignancies
- Hemophagocytic Lymphohistiocytosis (HLH)

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8
Q

B cell primary deficiencies

A
  • X-linked agammaglobulinemia
  • common variable immunodeficiency
  • selective IgA deficiency
  • specific antibody deficiency
  • transient hypogammaglobulinemia of infancy
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9
Q

X-linked Agammaglobinemia

A

Pathology:
- defect in Bruton’s tyrosine kinase (btk) signaling <- required for early B cell development in bone marrow
- complete deficiency in mature B cells

Symptoms:
- recurrent pyogenic infections: otitis media, sinusitis, conjunctivitis, pneumonia
- eventual anatomic destruction (lungs)
- no problems with viruses or intracellular bacteria
- diagnosed in young inants
- small tonsils and lymph nodes
- antibodies from vaccination are absent
- low levels of mature B cells in blood
- low IgM, IgG, IgA, IgE levels

Treatment:
- passive immunization

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10
Q

IgA deficiency

A

Pathology:
- most common immunodeficiency
- diverse genetics (20% inheritance)

Symptoms:
- only 50% symptomatic
- multiple respiratory, GI, GU infections
- not usually life threatening
- age of dx varies due to variability of symptoms
- higher risk for autoimmune disease (25% of symptomatic individuals), allergies (10% of symptomatics)

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11
Q

Common Variable Immunodeficiency (CVID)

A

Pathology:
- B cell phenotypically normal but unable to differentiate into Ig producing cells
- genetics are diverse (may be linked with IgA deficiency)
- relatively common (1:20,000)

Symptoms:
- multiple severe upper respiratory infections (sinopulmonary) with lymphadenopathy and polyarthritis of large joints
- low IgG, IgA, IgM levels
- bacterial infections predominate
- also recurrent herpesvirus, enterovirus, Giardia infections
- classic presentation is in 20s-30s with normal Ab levels until symptoms arise
- higher risk of malignancies in older patients (gastric carcinoma, lymphoma)

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12
Q

T cell/combined immunodeficiencies

A
  • 22q11.2 deletion (DiGeorge)
  • SCID (severe combined immunodeficiency)
  • Wiskott-Aldrich
  • Ataxia telangiectasia
  • hyper IgM syndrome
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13
Q

X-linked Hyper IgM Syndrome

A

Pathology:
- elevated IgM, no IgA, very low IgG
- defect in CD40L of T cells, preventing follicular B cells from receiving T cell help
- lack of germinal center reaction and class switching, affinity maturation, plasma and memory cells
- defect in macrophage activation due to lack of T cell CD40L ==> WBC counts do not rise during infection

Symptoms:
- susceptible to pyogenic infection (mainly respiratory)
- susceptible to opportunistic pathogens like Pneumocystic jivoreci
- usually teenagers begin to exhibit uncontrollable proliferation of IgM producing plasma cells
- low IgG, IgA, IgE; normal or elevated IgM

Treatment:
- monthly administration of immune globulin

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14
Q

Severe Combined Immunodeficiency (SCID)

A

Pathology:
- absence of T cells (or loss of T cell function) ==> combined effect on B cell function
- X-linked form of disease is most common (defect in T cell development)

Symptoms:
- fatal in young infants who are ill by 3mo, fail to thrive
- persistent thrush, extensive diaper rash, intractable diarrhea, cough
- persistent infections
- lack of secondary lymphoid organs
- no thymic shadow on chest X-ray

Treatment:
- bone marrow transplantation
- weekly gamma globulin therapy

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15
Q

SCID infections

A

T-cell (cell-mediated immune) deficiency:
- Bacteria: Listeria, Salmonella, enteric flora
- Mycobacteria including BCG
- Viruses: herpes, RSV, influenza, measles
- Fungi: Pneumocystis, Candida, cryptococcus, histoplasma

lack of T-cell help for B-cells (Ab deficiency):
- infections of upper respiratory, GI, GU tracts
- Bacteria: Strep pneumo, H flu, Neisseria meningitidis, Staph aureus, Pseudomonas, Campylobacter
- Mycoplasma, Ureaplasma
- Viruses: enteroviruses, rotavirus
- Protozoa: Giardia, cryptosporidium

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16
Q

X-linked SCID

A
  • defect of common gamma chain receptor; signaling required for T and NK cell development
  • lack of T cells and NK cells
  • B cells are present
  • screen: PCR detection of T cell receptor excision circles (TRECs) in newborns <- direct measure of thymnus function
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17
Q

Recombination Activating Gene (RAG) deficiency

SCID

A
  • RAG1, RAG2 deficiency = Omenn’s syndrome
  • RAG is required for developing T and B cells
  • patients lack both T cells and B cells, NK cells present
  • no TCR recombination (TREC negative) or BCR recombination (KREC negative)
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18
Q

Adenosine deaminase (ADA) deficiency

SCID

A
  • issue with purine synthesis salvage pathway: ADA catalyzes AMP ==> IMP
  • dAMP/dADP/dATP metabolites accumulate and kill developing lymphocytes
  • patients lack T and B cells, also lack NK cells
  • recurrent phenumonias, chronic diarrhea, slow growth
  • most infants die before age of 2 without treatment
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19
Q

DiGeorge Syndrome

A

Pathology:
- 22q11.2 deletion
- thymic hypoplasia/aplasia
- failure of development of 3rd and 4th pharyngeal pouches; may lack parathyroid glands

Symptoms:
- frequently have congenital heart disease
- mildly lymphopenic (decreased T cells, normal B cells), normal immunglobulin levels, variable lymphocyte response to mitogens
- lymph node paracortex is depleted

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20
Q

Bare Lymphocyte Syndromes (BLSI and BLSII)

A

BLSI:
- deficiency in peptide loading of MHC-I
- no positive selection of CD8+ T cells ==> low CD8+ count
- prone to viral infection (esp respiratory infections)

BLSII:
- deficiency in expression of MHC-II
- no positive selection of CD4+ T cells ==> low CD4+ count
- prone to bacterial infections

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21
Q

Wiscott-Aldrich syndrome

A

Pathology:
- defective cytoskeleton protein WASp ==> defective antigen presentation
- T cells and platelets defective in number and function
- defects in monocyte/macrophage motility and phagocytosis

Symptoms:
- purpura, eczema, recurrent encapsulated organism infections
- thrombocytopenia with small platelets
- normal or decreased IgG, IgM
- elevated IgA, IgE

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22
Q

Complement disorders

A

deficiency of classical components (C1, C4, C2):
- immune complex diseases

deficiency of mannose binding lectin:
- encapsulated bacterial infections
- sacchromyces cerevisiae

deficiencies of alternative pathway (factor D, B, C3):
- decreased opsonization ability
- encapsulated bacterial infections

C3 deficiencies:
- defective opsonization, leukocyte chemotaxis, bactericidal killing activity
- overwhelming encapsulated bacterial infections

defects in MAC:
- N. meningitidis infections
- decreased morbidity rates than C3 deficiencies

23
Q

Phagocytic primary disorders

A
  • severe congenital neutropenia
  • chronic granulomatous disease
  • leukocyte adhesion deficiency (LAD1 and LAD2)
  • Chediak-Higashi syndrome
24
Q

Leukocyte Adhesion Deficiency (LAD)

A

Pathology:
- LAD1: deficiency in CD18, affects late neutrophil extravasation events and phagocytosis
- LAD2: deficiency in fucose synthesis ==> lack of sialyl-Lewis X ==> neutrophil rolling affected

Symptoms:
- severe periodontitis, recurrent oral and genital mucosal infections
- S. aureus, candida, aspergillus
- slow wound healing and scarring
- normal antibodies and T cell function

Test:
- flow cytometric analysis to detect CD18 or sialyl-Lewis X on cell surface

25
Q

Chronic Granulomatous Disease

A

Pathology:
- genetic defect that inactivates NADPH oxidase

Symptoms:
- recurrent/persistent bacterial infections of skin, lungs, lymph nodes, viscera despite aggressive antibiotic therapy
- excessive granulomas in all tissues

Treatment:
- daily dose of antibiotics (eg trimethoprim-sulfamethoxazole)
- treated with IFN-y which reduces frequency of infection
- bone marrow transplant
- gene therapy

26
Q

Chediak-Higashi syndrome

A

Pathology:
- defect in LYST or CHS1 gene
- defect in microtubule function ==> prevents lysosomes from fusing with phagosomes

Symptoms:
- oculo-cutaneous albinism
- high incidence of lymphoreticular neoplasms
- recurrent pyogenic infections
- affects platelet function (bleeding/bruising)

Treatment:
- aggressive antibiotics
- bone marrow transplant

27
Q

Immunosuppressive drug classes

A

1) Glucocorticoids (prednisone, dexamethasone)

2) Immunophilin ligands
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- mTOR inhibitors (sirolimus)

3) Cytotoxic drugs

4) Inhibitors of nucleotide synthesis
- Mycophenolate mofetil (MMF)
- Azathioprine

5) Anti-TNF-a agents

6) Antibodies
- Basiliximab

28
Q

Glucocorticoids

A

Drugs: Prednisone, Dexamethasone

MOA:
- decrease synthesis of signaling molecules in immune responses (prostaglandins, leukotrienes, cytokines, platelet activating factor)
- inhibit T cell proliferation
- cytotoxic to certain lymphocytes

Uses:
- autoimmune diseases
- transplantation

Toxicity:
- adrenal suppression
- growth inhibition
- muscle wasting
- osteoporosis
- salt retention
- glucose intolerance
- psychosis

29
Q

Immunophilin ligands

A

Immunophilins:
- cytoplasmic proteins that play critical roles in T cell responses to TCR activation and cytokines

Calcineurin inhibitors:
- Cyclosporine
- Tacrolimus

mTOR inhibitors:
- Sirolimus

Uses:
- solid organ transplanation
- GVH disease in bone marrow transplant
- autoimmune diseases (rheumatoid arthritis, uveitis, psoriasis)
- asthma

30
Q

Cyclosporine & Tacrolimus

A

MOA:
- Cyclosporine binds to cyclophilin, Tacrolimus binds to FKBP ==> inhibition of calcineurin ==> inhibition of NFAT ==> inhibition of gene transcription ==> inhibition of IL-2 production by T cells upon TCR activation

Pharmacokinetics:
- Cyclosporine has a long half-life; slow hepatic metabolism by CYP450 system
- drug-drug interactions affect metabolism

Toxicity: “CNN = Cyclosporin-Nephrotoxicity-Neurotoxicity”
- nephrotoxicity
- neurotoxicity (limb paresthesias, distal tremors, hallucinations, seizures)
- hypertension

31
Q

Sirolimus

A

MOA:
- Sirolimus binds to FKBP ==> inhibition of mTOR ==> blocks cell proliferation at G1-S transition
- inhibits response of T cells to cytokines
- inhibits C cell proliferation, Ab production, responses to colony-simulating factor

Toxicity: “the kidneys ‘SIRvive’”
- hepatotoxicity
- profound myelosuppression (thrombocytopenia)

32
Q

Cytotoxic agents

A
  • Cyclophosphamide
  • Azathioprine
  • Cytarabine
  • Dactinomycin
  • Methotrexate
  • Vincristine
33
Q

Cyclophosphamide

Alkylating agent

A

MOA:
- transformed by CYP450 to alkylating agent cytotoxic to proliferating lymphoid cells
- inhibits established immune response

Uses:
- autoimmune diseases (hemolytic anemia)
- Ab-induced red cell aplasia
- bone marrow transplants

Toxicity:
- large doses cause pancytopenia
- hemorrhagic cystitis (bladder infection)

34
Q

Azathioprine

A

MOA:
- transformed to the antimetabolite mercaptopurine ==> inhibits purine metabolism (IMP)
- cytotoxic in early phases of lymphoid cell proliferation

Uses:
- autoimmune diseases (lupus, rheumatoid arthritis)
- renal homografts

Toxicity:
- myelosuppression (pancytopenia)
- hepatotoxicity is dose-limiting
- assoc. with increased incidence of cancer
- toxicity may be increased with concurrent use of allopurinol (gout prevention), so need to reduce dose to 25-33%

35
Q

Cytarabine

A

MOA:
- inhibits DNA polymerase
- S-phase specific

Uses:

Toxicity:

36
Q

Dactinomycin

A

MOA:
- intercalate DNA

Uses:

Toxicity:

37
Q

Methotrexate

A
  • binds to site of DHFR, inhibiting formation of THF and IMP (d.n. purine synthesis)
  • hepatotoxicity
  • tx with Leucovorin
  • clearance depends on renal function
  • resistance via increased expression of P-glycoprotein transporter

“meDHROotrexate”

38
Q

Vincristine

A

MOA:
- inhibition of microtuble assembly (tubulin)
- M-phase specific

Uses:

Toxicity:

39
Q

Inhibitors of nucleotide synthesis

A
  • Leflunomide
  • Mycophenolate mofetil (MMF)
40
Q

Leflunomide

A

MOA:
- inhibits dihydroorotic acid dehydrogenase (DHODH) ==> inhibition of pyrimidine synthesis
- arrests lymphocytes in G1 phase

Uses:
- rheumatoid arthritis

Toxicity:
- liver damage
- renal impairment
- teratogenic
- cardiovascular effects

41
Q

Mycophenolate mofetil (MMF)

A

MOA:
- converted into mycophenolic acid ==> inhibition of inosine monophsphate dehydrogenase (IMPDH) ==> inhibition of de novo purine synthesis
- suppresses activation of T and B cells

Uses:
- kidney, liver, heart transplantation
- use with low-dose cyclosporine to reduce cyclosporine-induced nephrotoxicity

Toxicity:
- GI (diarrhea)
- myelosuppression (esp neutropenia)

42
Q

Anti-TNF-a agents

A
  • Etanercept
  • Infliximab
  • Adalimumab
  • Thalidomide
43
Q

Etanercept

A

MOA:
- binds to TNF-a
- decreases formation of interleukins and adhesion molecules ==> decreased leukocyte activation

Uses:
- rheumatoid arthritis
- psoriatic arthritis

Toxicity:
- hypersensitivity
- increased rate of serious infection and lymphoma

44
Q

Infliximab

A

MOA:
- neutralizes TNF-a

Uses:
- Crohn’s disease
- rheumatoid arthritis
- ulcerative colitis

Toxicity:
- infusion reactions
- increased rate of infection

45
Q

Adalimumab

A

MOA:
- neutralizes TNF-a

Uses:
- rheumatoid arthritis

46
Q

Thalidomide

A

MOA:
- anti-inflammatory, immunomodulatory effects

Uses:
- sedative, anti-nausea medication that was withdrawn from the market in 1960s

Toxicity:
- teratogenic

47
Q

Antibodies

A
  • Rho(D) immune globulin
  • Muromonab-CD3
  • Daclizumab
  • Basiliximab
48
Q

Rho(D) immune globulin

A

MOA:
- blocks primary B cell response against the Rho(D) Ag via blocking Ag recognition

Uses:
- prevention of Rh hemolytic disease of the newborn in subsequent pregnancies

49
Q

Muromonab-CD3 (OKT3)

A

MOA:
- binds to CD3 Ag on T cells
- blocks killing action of cytotoxic T cells

Uses:
- renal transplanation

Toxicity:
- fever, chill, dyspnea
- pulmonary edema
- hypersensitivity reactions

50
Q

Basiliximab (& daclizumab)

A

MOA:
- IL-2 antagonist, preventing activation of T-cells by IL-2

Uses:
- used in combo with other immunosuppressants (glucocorticoids, cyclosporine) to prevent renal transplant rejection

51
Q

Purine nucleoside phosphorylase (PNP) deficiency

A
  • autosomal recessive
  • catalyzes guanosine ⇒ guanine; inosine ⇒ hypoxanthine
  • accumulation of dGTP, IMP
  • affects T cells only
  • recurrent infections, neurodevelopmental delay
52
Q

Lesch-Nyhan syndrome

A

Pathology:
- X-linked recessive
- mutation in hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) gene ⇒ complete deficiency of HGPRT activity
- inability to salvage hypoxanthine or guanine (guanine => GMP)
- free purine bases are degraded into uric acid instead ⇒ hyperuricemia

Symptoms:
- gout and kidney problems
- neurologic features (self-mutilation, involuntary movements)
- patients at risk for gout

Treatment:
- Allopurinol: inhibition of xanthine oxidase
- generous hydration

53
Q

Gout

A

Pathology:
- renal issues (or lactic acidosis, lead) ⇒ underexcretion of uric acid ⇒ hyperuricemia
- increased PRPP synthetase activity ⇒ increased purine synthesis ⇒ increased purine degradation ⇒ increased uric acid production

Symptoms:
- hyperuricemia
- recurrent attacks of acute arthritic joint inflammation due to deposition of monosodium urate crystals
- crystal deposition (tophi) seen in soft tissue and kidney
- negatively birefringint urate crystals in joint synovial fluid

Treatment:
- Allopurinol: accumulation of hypoxanthine and xanthine, which are more soluble than uric acid

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