Immunodeficiencies & Immunosuppressants

Question 1

Asthma

Answer 1

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

Question 2

Congenital (primary) vs acquired (secondary) immunodeficiencies

Answer 2

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

Question 3

B-cell immunodeficiency clinical manifestations

Answer 3

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

Question 4

T cell immunodeficiency clinical manifestations

Answer 4

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

Question 5

Phagocyte immunodeficiency clinical manifestations

Answer 5

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

Question 6

Complement deficiency clinical manifestations

Answer 6

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

Question 7

NK cell deficiency clinical manifestations

Answer 7

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

Question 8

B cell primary deficiencies

Answer 8

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

Question 9

X-linked Agammaglobinemia

Answer 9

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

Question 10

IgA deficiency

Answer 10

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)

Question 11

Common Variable Immunodeficiency (CVID)

Answer 11

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)

Question 12

T cell/combined immunodeficiencies

Answer 12

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

Question 13

X-linked Hyper IgM Syndrome

Answer 13

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

Question 14

Severe Combined Immunodeficiency (SCID)

Answer 14

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

Question 15

SCID infections

Answer 15

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

Question 16

X-linked SCID

Answer 16

• 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

Question 17

Recombination Activating Gene (RAG) deficiency

SCID

Answer 17

• 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)

Question 18

Adenosine deaminase (ADA) deficiency

SCID

Answer 18

• 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

Question 19

DiGeorge Syndrome

Answer 19

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

Question 20

Bare Lymphocyte Syndromes (BLSI and BLSII)

Answer 20

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

Question 21

Wiscott-Aldrich syndrome

Answer 21

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

Question 22

Complement disorders

Answer 22

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

Question 23

Phagocytic primary disorders

Answer 23

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

Question 24

Leukocyte Adhesion Deficiency (LAD)

Answer 24

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

Question 25

Chronic Granulomatous Disease

Answer 25

**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

Question 26

Chediak-Higashi syndrome

Answer 26

**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

Question 27

Immunosuppressive drug classes

Answer 27

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**

Question 28

**Glucocorticoids**

Answer 28

**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

Question 29

Immunophilin ligands

Answer 29

**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

Question 30

**Cyclosporine & Tacrolimus**

Answer 30

**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

Question 31

**Sirolimus**

Answer 31

**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)

Question 32

Cytotoxic agents

Answer 32

- Cyclophosphamide - Azathioprine - Cytarabine - Dactinomycin - Methotrexate - Vincristine

Question 33

Cyclophosphamide | Alkylating agent

Answer 33

**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)

Question 34

**Azathioprine**

Answer 34

**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%

Question 35

Cytarabine

Answer 35

**MOA:** - inhibits DNA polymerase - S-phase specific **Uses:** **Toxicity:**

Question 36

Dactinomycin

Answer 36

**MOA:** - intercalate DNA **Uses:** **Toxicity:**

Question 37

Methotrexate

Answer 37

- 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”

Question 38

Vincristine

Answer 38

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

Question 39

Inhibitors of nucleotide synthesis

Answer 39

- Leflunomide - Mycophenolate mofetil (MMF)

Question 40

Leflunomide

Answer 40

**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

Question 41

**Mycophenolate mofetil (MMF)**

Answer 41

**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)

Question 42

Anti-TNF-a agents

Answer 42

- Etanercept - Infliximab - Adalimumab - Thalidomide

Question 43

Etanercept

Answer 43

**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

Question 44

Infliximab

Answer 44

**MOA:** - neutralizes TNF-a **Uses:** - Crohn's disease - rheumatoid arthritis - ulcerative colitis **Toxicity:** - infusion reactions - increased rate of infection

Question 45

Adalimumab

Answer 45

**MOA:** - neutralizes TNF-a **Uses:** - rheumatoid arthritis

Question 46

Thalidomide

Answer 46

**MOA:** - anti-inflammatory, immunomodulatory effects **Uses:** - sedative, anti-nausea medication that was withdrawn from the market in 1960s **Toxicity:** - teratogenic

Question 47

Antibodies

Answer 47

- Rho(D) immune globulin - Muromonab-CD3 - Daclizumab - Basiliximab

Question 48

Rho(D) immune globulin

Answer 48

**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

Question 49

Muromonab-CD3 (OKT3)

Answer 49

**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

Question 50

**Basiliximab** (& daclizumab)

Answer 50

**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

Question 51

Purine nucleoside phosphorylase (PNP) deficiency

Answer 51

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

Question 52

Lesch-Nyhan syndrome

Answer 52

**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

Question 53

Gout

Answer 53

**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