Immunology

Question 1

Immune dysregulation, polyendocrinopathy, and enteropathy X-linked

(IPEX)

Answer 1

FoxP3 mutation (Treg express CD4, CD25, and FoxP3). A fatal autoimmune disorder characterized by a triad of watery diarrhea (~100%), eczema (~95%), and endocrinopathy (type I DM [~75%], cytopenias [~50%], thyroiditis [~40%]).

Diagnosis: Flow cytometry for intracellular FoxP3 expression in CD4+/CD25+ T cells (Tregs). The definitive diagnostic test is the mutation analysis FoxP3 gene.

Therapy: Immunosuppression (e.g. sirolimus) prior to definitive therapy. Definitive/curative therapy: HSCT.

Question 2

Which TLRs are present in the intracellular compartment and implicated in HSV1 encephalitis?

Answer 2

TLR 3, 7, 8, and 9

Question 3

Antigen processing and MHC Presentation (MHC I Pathway)

Answer 3

Key Factor: Viruses develop strategies to evade the MHC I presentation. HSV can block TAP transportation, CMV can remove MHC I form ER.

Question 4

What enzyme is required for somatic hypermutation?

Answer 4

Key fact: CD40 ligand - CD40 interaction stimulates AID, which is crucial for SHM and isotype switching

Question 5

What cytokines induce IgD class switching?

Answer 5

None

Do not require isotype switching, exact function unknown, B-cell maturation marker

Question 6

Immune complexes tend to be the largest under which of the following conditions?

Answer 6

Extreme antibody excess

Question 7

What is released by epithelial cells to maintain mucosal mast cells at the airway and skin surface?

Answer 7

Stem cell factor (SCF)

Question 8

IgG and IgM activate which complement pathway?

Answer 8

Classical pathway

Question 9

What is the target of RF, and what is the most common RF Ig isotype?

Answer 9

RF is an antibody against the Fc portion of IgG. RF is most commonly IgM.

Question 10

Chemokines and Associated Conditions

Answer 10

Question 11

Peripheral Tolerance and Maintenance

(T-lymphocytes)

Answer 11

Same outcomes as central tolerance: Anergy, deletion, or regulation. Lack of the second signal produces the anergy of the peripheral T lymphocytes (maintain by blockade of TRCsignaling, ubiquitin ligases, and inhibitor costimulatory molecules [e.g., CTLA-4 and PD-1]).

Maintenance of tolerance: Non-activated DC do not express receptors → Ag presented to T lymphocytes will not have a second signal ⇒ Tolerance

Key Fact: Treg (express CD4, CD25, FofP3) is critical in maintaining normal immune function.

Question 12

Ig Structure

(heavy chains, light chains, Ig Fragments, hinge regions, variable regions, constant regions)

Answer 12

Heterodimer w/ 2 identical light chains and 2 identical heavy chains connected with disulfide bonds.

_{<span><b>Heavy chains</b></span>} (γ, α, μ, ε, δ): IgG (IgG1, IgG2, IgG3, IgG4), IgA, and IgD have 3 C_H domains. IgA and IgE have 4 C_H domains.

_{<span>Light chains</span>} (κ [chromosome 2] and λ [chromosome 22]): An IgG molecule has either κκ (60%) or λλ (40%) but never 1 of each.

Ig Fragments: Papain: cleaves Ig above the hinge ⇒ 2 Fab (can bind but not cross-link); Pepsin: cleaves Ig below the hinge ⇒ Fab’₂ (binds and cross-link). Neither Fab nor Fab’₂ will fix complement or bind to the Fc receptor on the cell surface.

Hinge regions: Proline-rich and provide Ig flexibility.

Variable regions (V_L and V_H): Ag-binding site (CDRs [there are 3 in each V region, CDR3 is the most variable])

Constant regions (C_H and C_L): C-terminal. Only C_H mediates effector functions (binding to Fc receptors or binding complement).

Glycosylation: Critical to maintaining structure/stability/function (e.g., IgG has its glycosylation site at the Cγ domain, deglycosylated IgG cannot bind to FcγRs and C1q ⇒ ADCC and complement activation.

Question 13

Classical Complement Pathway

Answer 13

1. Activate by C1 binding to Ag-Ab complexes
2. C1q binds to the Fc portion of an Ig cross-linked Ag
3. Binding affinity of C1q: IgM > Ig3 > Ig1 > Ig2
4. C1q - C1r → C1s → C4 / C2 ⇒ C4b2a (C3 convertase of the CP)
5. C1 inhibitor → C1r - C1s (regulating the pathway)
6. C4b → DAF (CR1 and C4BP) ⇒ Blocks further progression of the cascade

Question 14

Which somatic recombination process introduces the greatest diversity in immune receptors and which enzyme is important in this process?

Answer 14

Junctional diversity; TdT enzyme is important in this process.

Question 15

What cytokines induce IgG (1, 2, 3, 4) class switching?

Answer 15

• IgG1: INFγ and IL-4 (T_h1 response, opsonization, best for ADCC)
• IgG2: INFγ and TGFβ (antipolysaccharide-Ab, the latest to reach an adult level of all IgG subclasses)
• IgG3: INFγ (shortest half-life in IgG-subclasses, opsonization)
• IgG4: IL-4 and IL-13 (antipolysaccharide-Ab, elevated in immunotherapy)

Question 16

IPEX-like Disorders

Answer 16

IPEX-like Disorder (CD25 deficiency): Chronic diarrhea and villous atrophy in infancy, type 1 DM, auto-antibodies, lymphadenopathy, hepatosplenomegaly. Early-onset CMV pneumonitis, candidal esophagitis, chronic GI infections.

IPEX-like Disorder (STAT5b Deficiency): Early-onset diarrhea, eczema, lymphocytic interstitial pneumonitis. Dwarfism, prominent forehead, saddle nose, and high pitched voice. Recurrent PCP, herpes, and varicella infections.

Decreased CD25 expression and Tregs, normal GH but depressed IGF-1 levels.

Question 17

Anti-C1q Antibody

Answer 17

Autoantibody to the collagen-like region of C1q found in patients with hypocomplementemic urticarial vasculitis (HUVS → responsive to Plaquenil)

Question 18

Structure of MHC Class I and Class II Molecules (Table)

Answer 18

Question 19

AIRE

Answer 19

The autoimmune regulatory (AIRE) gene is expressed in the thymus. This gene promotes the expression of nonthymic tissue antigens in the thymus.

Key Fact: Mutation in the AIRE gene produces disorders such as autoimmune polyglandular syndrome (APS). Lymphocytes are not deleted or tolerized to endocrine-related self-antigens. The endocrine organs are attacked by autoreactive T lymphocytes and autoantibodies.

Question 20

How long after drug initiation does serum sickness typically develop in a patient with no prior exposure to the medication in question?

Answer 20

1-3 weeks (other option 4 - 10 days)

Question 21

What are the primary immunoglobulins involved with type II hypersensitivity?

Answer 21

IgM and IgG

Question 22

What CD molecules are in the BCR coreceptor?

Answer 22

CD21, CD19, and CD81

Question 23

What has been shown to be the earliest event in an active Arthus reaction?

Answer 23

Immune complex and complement deposition

Question 24

Lectin Complement Pathway

Answer 24

1. Activitated in the absence of Ab
2. Mannose-binding lectin (MBL) binds to mannose residues on microbial polysaccharides, MBL-associated protease-1 and -2 → cleaves C4 and C2 ⇒ C3 convertase C4b2a
3. C3 convertase cleaves C3 to C3b which binds to the convertase and forms C5 convertase (C3bBb3b in the AP and C4b2a3b in the CP and LP)

Question 25

Where does omalizumab bind?

Answer 25

Omalizumab binds to the **IgE Cɛ3** domains outside of the FcɛRI-binding site

Question 26

Seven Ts of passive immunity

Answer 26

Question 27

What is the only Ig to cross the placenta and to what receptor does it bind?

Answer 27

**IgG** ## Footnote Binds to neonatal Fc receptor (FcRn) Nadir around 4 - 6 months after birth

Question 28

Central B-lymphocyte Tolerance (*Ig gene rearrangement and key B lymphocyte development checkpoints*)

Answer 28

Precursor B lymphocyte is exposed to self-antigens in the **_BM_**. **_Three fates:_** apoptosis (negative selection), **receptor editing** (*RAG1/RAG2*), anergy. **Order Ig rearrangement: 1) D → J_H** (both chromosomes); **2) V_H → DJ_H** (one chromosome); **3) V_κ **→ **J_κ** (one chromosome); **3) V_λ → J_λ **(one chromosome). **Key Fact:** The κ light chains are rearranged first. If receptor editing is needed, a λ light chain will be used.

Question 29

Which TLR does not signal through MyD88?

Answer 29

TL3 and part of TLR4

Question 30

B-1 B Cells | (characteristics)

Answer 30

* Constitute 30-50% of the B cells in the pleural and peritoneal cavities * Different developmental lineage compared to B-2 and marginal zone B cells * **_Peripheral cells_** * Express very low levels of TdT (little N-nucleotide diversity) * Surface expression of **CD20, CD27, and CD43**, and are CD38^{low/intermediate} * Secrete antibody **_without antigen stimulation_** (constitutively secrete antibody) * Limited antigen receptor repertoire that favors binding to _microbial carbohydrate antigens_

Question 31

Superantigens

Answer 31

Antigens that activate a large number of polyclonal T lymphocyte by binding outside the **MHC II** antigen cleft (individual with **Vβ**). Cause massive cytokine release). E.g., *S aureus* (**SEB** [food poisoning], **SEC2** [food poisoning], **TSST** [Toxic shock syndrome]), *S pyogenes* (**SPE-C** [Streptococcal toxic shock syndrome]).

Question 32

What immunoglobulin fixes complement most efficiently?

Answer 32

IgM

Question 33

Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy (**APECED**)/Autoimmune Polyendocrinopathy Syndrome Type 1 (**APS1**)

Answer 33

**Genetics:** Autosomal recessive defect in AIRE **APECED/APS1:** Autoimmune polyendocrinopathy (e.g., hypothyroidism [85%], adrenal failure [72%], ovarian failure [60%], etc.), Candidiasis (mucocutaneous candidiasis [~100%]), Ectodermal Dystrophy (Nail dystrophy). **Diagnosis: _AIRE mutation_**. **Evaluation:** Monitoring endocrine function, evaluation for autoimmunity. **_Autoantibodies to α-IFN_** are seen in the majority of patients, autoantibodies to IL-17/IL-22 found in some patients. **Therapy:** Antifungals, replacement therapy for endocrine diseases, lung/liver/GI autoimmunity may require treatment with rituximab or azathioprine.

Question 34

Abacavir

Answer 34

HLA-B\*5701

Question 35

Late Steps of Complement Activation

Answer 35

1. C5 convertase cleaves C5 and initiates the formation of the MAC; C5a is released (most potent mediator of basophils and cutaneous mast cell degranulation [C5a \> C3a \> C4a]) 2. MAC is formed by (C5b - 8) polyC9; it creates pores in the membrane and induces cell lyses 3. C9 is structurally homologous to perforin 4. **S Protein and CD59** inhibit the formation of the MAC

Question 36

CD4 and CD8 cytoplasmatic signal

Answer 36

Src family tyrosine kinase (**lck**) → required for T-lymphocyte activation and maturation Lck → phosphorylates ITAMs in CD3s and ζ proteins facilitating the recruitment and activation of **ZAP70** **Key fact:** _ZAP-70 deficiency_ ⇒ **SCID (T^-/B⁺/NK⁺)**

Question 37

Which integrin molecule is important for gut homing by binding to MAdCAM?

Answer 37

**α4β7**

Question 38

Types of Antigens

Answer 38

Question 39

**EBV Induced Lymphoproliferative Syndromes** (XLP1 and XLP2)

Answer 39

**_XLP1:_** X-linked defect in **_SH2D1A/SAP_** gene encoding an adaptor protein that regulates intracellular signaling, iNKT cells virtually absent, NK cell activation via 2B4 is abnormal, lack of EBV specific cytotoxic T cells over time, switched memory (CD27+) B cells low. **_XLP2:_** X-linked defect XIAP gene encoding X-linked inhibitor of apoptosis, iNKT cells low. **Clinical Manifestations** **XLP -1** **XLP-2** HLH with EBV 45% ~50% Lymphoma (majority B cell) ~30% 0% Hypo-/dysgammaglobulinemia (after EBV) ~40% ~30% Splenomegaly without HLH \<10% ~90% Hemorrhagic colitis 0% ~20%

Question 40

What two molecules inhibit MAC (CD55) formation?

Answer 40

CD 59 (DAF) and S protein

Question 42

Alternative Complement Pathway (figure)

Answer 42

1. Activated by C3b binding to various activating surfaces (e.g., microbial surfaces). 2. **Factor D** cleaves **Factor B** ⇒ **C3bBb** (C3 convertase of the AP) 3. **_Properdin_** is the only known positive regulator of complement 4. Regulation of this pathway occurs through **_Factor I_**-mediated cleavage of C3b 5. Factor H, membrane cofactor protein (MCP/CD46), and decay-accelerating factor (DAF/CD55) serve as cofactors

Question 43

B-cell coreceptor complex

Answer 43

**CD21 - CD19 - CD81** when CD21 interacts with C3d, the complex is brought to the BCR

Question 44

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 44

**CD59 (MAC) and CD55 (DAF)**

Question 45

Immunogen (**_lipids_**)

Answer 45

Activate NKT via CD1

Question 46

Peripheral B-lymphocyte tolerance

Answer 46

Chronic antigen recognition **downregulates** **_CXCR5_**, inhibiting B-lymphocyte homing, and interaction with T lymphocytes ⇒ cell death.

Question 47

Fc Receptors (Table)

Answer 47

Members of the Ig superfamily. Each FcR functions as a receptor specific for the C_H region of the Ig molecule.

Question 48

Autoimmune lymphoproliferative syndrome | (**ALPS**)

Answer 48

**_Mutation:_** **Fas or caspase 10** → Autoimmune lymphoproliferative syndrome (ALPS). Lymphocytes do not know when to die. They accumulate in lymph organs. There is a lack of tolerance, producing autoimmune problems. **_Diagnosis:_** Non-malignant lymphadenopathy, Increased (\>1.5%) α/β DNT cells plus either, defective *in vitro* FAS induced lymphocyte apoptosis, genetic defect (_the majority in **FAS**_). **Clinical features:** Autoimmune disease (cytopenias), typical histological findings, family history of similar clinical findings, lymphoma in the family (increased risk for lymphoma in ALPS). **Biomarkers​ (Fas mutation):** Increase serum vitamin B12, IL-10, soluble FasL.

Question 49

What is released by Th2 cells to stimulate mast cell proliferation?

Answer 49

**IL-9**

Question 50

Affinity

Answer 50

Strenght of the binding between each molecule of Ig and antigen epitopes (K_d, lower K_d indicates higher affinity)

Question 51

What is the most important cytokine for the T-lymphocyte survival signal, and receptor?

Answer 51

**IL-2 and its receptor CD25**

Question 52

**TRC Complex**

Answer 52

TRC complex consists of TCR, CD3, and two zeta (ζ) chains **Antigen-signaling:** ITAMS

Question 53

Apoptosis

Answer 53

1. Extrusion of vesicles containing cellular components 2. Preservation of an intact cell membrane 3. Fragmentation of DNA (karyorrhexis) **Key Fact:** Extrusion of naked DNA into the extracellular environment is a feature of "ETosis", a form of cell death distinct from apoptosis which leads to the generation of extracellular traps.

Question 54

NKT Cells

Answer 54

Express NK cell and T-lymphocyte markers **Key fact:** NKT cells recognize lipids in the context of CD1

Question 55

Ig Forms

Answer 55

Two forms of IgG exist that differ in the aa sequence of the C-terminal end of the C_H: * **Membrane-bound Ig:** Attached to B-lymphocytes (transmembrane region). Seve as B-lymphocyte Ag receptors ⇒ B-lymphocyte activation. * Secreted Ig: LAcks transmembrane region. Circulate in plasma, mucosal sites, and GI fluids. Monomers (IgG), dimers (IgA), pentamers (IgM).

Question 56

MHC

Answer 56

MHC molecules share certain features: 1. Each MHC molecule has one binding site 2. MHC molecules are bound to cell membranes 3. Interaction with T lymphocyte requires direct contact 4. **Key fact**: MCH molecules are **co-dominant** (MHC from _both parents_ is expressed on cell surfaces)

Question 57

Facts about TSLP

Answer 57

* Epithelial cells and mast cells release TSLP * TSLP acts on immature dendritic cells to mature. * TSLP stimulates the release of CCL17, which attracts Th2 cells via CCR4. **Key Fact:** TSLP does not directly act on eosinophils and B lymphocytes. TSLP directly acts on Th2 cells which then release cytokines that act on eosinophils and B lymphocytes.

Question 58

Immunoglobulin Classes/Subclasses (Table: functional activity and distribution)

Answer 58

Question 59

**C3 Nephritic Factor**

Answer 59

**Autoantibody that binds and stabilizes C3bBb** (results in unregulated consumption of C3) SLE, associated with MPGN and partial lipodystrophy

Question 60

ALPS

Answer 60

Increased (\>1.5%) alpha/beta DNT

Question 61

What is the MHC II binding site?

Answer 61

**β2 region**

Question 62

Selected SNPs Associated with Development of Atopic Disease (Table)

Answer 62

Question 63

Costimulation between **_APC_** and T-lymphocytes (Table)

Answer 63

**Key Fact:** CD3 deficiency ⇒ SCID

Question 64

What is the MHC I binding site?

Answer 64

**α3 region**

Question 65

Which TLR binds lipopolysaccharide (LPS) on gram-negative bacteria?

Answer 65

**TLR 4**

Question 66

What is the Ig class with the highest total body concentration and daily production?

Answer 66

**IgA** ## Footnote It may take several years for IgA to reach adult levels. In the GI tract, IgA is produced by plasma cells in the lamina propria and is transported across the mucosal epithelium by **poly-Ig receptor** _(transcytosis)_.

Question 67

What immunoglobulin has the shortest half-life?

Answer 67

IgG3

Question 68

αβ TCRs | (characteristics)

Answer 68

Heterodimer of an α and β chain (each consist of a variable [V, determine CDR] domain, a constant [C] domain, and a transmembrane hydrophobic region). **V_β** → binding site for superantigens. **Key Fact:** αβ TCRs recognize a single Ag only in the context of an HLA molecule. The receptor **has no signaling** ability and requires accessory molecules for signal transduction.

Question 69

What cytokines are released by Th2 cells?

Answer 69

**IL-4, IL-5, IL-9, and IL-13**

Question 70

What is the only X-linked complement component deficiency?

Answer 70

**Properdin** (only known positive regulator of complement) Complement deficiencies are generally autosomal recessive

Question 71

Ig superfamily

Answer 71

TCR, MHC molecules, CD4, CD8, CD19, B7-1, B7-2, Fc receptors, KIR, and VCAM-1

Question 72

Why is measuring exhaled nitric oxide more useful as a marker of asthma than allergic rhinitis?

Answer 72

**_Nitric oxide is elevated in patients with allergic rhinitis_**. Nitric oxide is increased further during the late response to inhaled allergen. There is an increased expression of inducible nitric oxide synthase in airway epithelial cells.

Question 73

In resting Th2 cells, GATA3 is localized to the cytoplasm. What causes phosphorylation of GATA3 so that GATA3 is imported to the nucleus and binds to the promoter region of Th2 cytokine genes to activate gene expression and cause allergic inflammation?

Answer 73

Interaction with antigen-presenting dendritic cells activates the T cell receptor (CD3) and costimulatory molecule CD28 causing p38 mitogen-activated protein kinase (MAPK) signal transduction. **Key Fact:** When IL-4 and IL-13 stimulate Jak1 and Jak3 to phosphorylate STAT6, GATA3 is activated (but not specifically moved from the cytoplasm to the nucleus)

Question 74

Which chemokine receptor is associated with **_WHIM_** (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome?

Answer 74

CXCR4

Question 75

Factor H Deficiency

Answer 75

**HUS, MPGN, and ARMD**

Question 76

Fas ligand | (**FasL/CD95L**)

Answer 76

Cells presenting self-antigen w/o innate response or costimulation have other receptors on their surfaces, such as **FasL/CD95L** on **_T lymphocytes_**. **FasL:** Upregulated on repeatedly activated T lymphocytes. **Interacts** w/ **Fas/CD95** same cell or nearby cell) → deletion/death (Fas : FasL signals through the **_caspase_** system). Mutation Fas or **_caspase 10_** **→** Autoimmune lymphoproliferative syndrome (ALPS)

Question 77

Which component is shared by IL-4 and IL-13 receptors?

Answer 77

IL-4 Rα, which is targeted by dupilumab

Question 78

CHARGE syndrome

Answer 78

Infants with the **_CHARGE_** (*CHD7 gene*) association share phenotypic features with patients with 22qDS, including _cardiac defects, cleft palate, and hearing loss_. ***CHARGE ≠ DGS:*** Coloboma, choanal atresia, genital anomalies, and _lack of 22q11 deletion_.

Question 79

Anaphylatoxins

Answer 79

**C5a, C4a, and C3a** * **C5a** is the most potent mediator of basophils and cutaneous mast cell degranulation (C5a \> C3a (only chemotactic for eosinophils) \> C4a)

Question 80

BCR Src Kinases

Answer 80

**Lyn, Fyn, and BTK** (unique to lymphocytes) Like in the TCR, they phosphorylate the ITAMs, providing a docking site for **Syk** (ZAP-70 analog) Key Factor: _Mutation in BTK_ ⇒ **_Bruton's agammaglobulinemia or XLA_** → Failure B-cell maturation

Question 81

Isotype Class Switching

Answer 81

Results in deletion of the constant region genes between Cμ and the new express heavy chain class/subclass

Question 82

What is the half-life of the Ig Isotypes (days)?

Answer 82

* IgG1: 23 days * IgG2: 23 days * IgG3: 8 days * IgG4: 23 days * IgA (IgA1 and IgGA2): 6 days * IgM: 5 days * IgD: 3 days * IgE: 2 days

Question 83

What is the most variable part of the Ig molecule?

Answer 83

**CDR3**

Question 84

T cells inside the thymus (*differentiation*)

Answer 84

Question 85

What are the four families of chemokines?

Answer 85

* C * CC → Eosinophils, Basophils, and Monocytes ⇒ ALLERGY * CXC →PMNs ⇒ INFLAMATTION * ELR - angiogenic, act through **_CXCR2_** * _Non-ELR - angiostatic, acts via CXCR3B, induced interferons__​_ * CX3 **Key Fact:** * Homeostatic: CCL19/CCL21 → CCR7 → Lymphocyte homing * Inflammatory: CCL17/CCL22 → CCR4 → pro T_h2 response

Question 86

What is released by epithelial cells to act on CCR4 to attract Th2 cells?

Answer 86

CCL17 and CCL22

Question 87

What disease presents with early-onset **_hypogammaglobulinemia with autoimmunity and immune dysregulation_**?

Answer 87

Lipopolysaccharide responsive beige-like anchor protein (**_LRBA_**) deficiency. *LRBA maintains intracellular stores of CTLA4, which can stop T-cell activation*. ## Footnote LRBA deficiency causes an AR combined immunodeficiency with **_severe autoimmune and inflammatory manifestations_**, including _IBD and autoimmune cytopenias_. Chronic diarrhea is a frequent and often severe symptom. **Kef Fact:** CTLA4 deficiency is similar to LRBA-deficient patients

Question 88

What interleukin is excessively produced in cryopyrinopathies?

Answer 88

**IL-1β**

Question 89

Contact activation pathway is initiated by which factor?

Answer 89

Factor XII

Question 90

Avidity

Answer 90

The net effect of affinity and valance (overall strength of the binding between Ig and antigen). A **low-affinity** IgM can produce a ***high-avidity*** interaction by simultaneous binding to multiple antigen epitopes through 10 contact sites on each IgM molecule.

Question 91

Important Chemokine Ligands and Receptors (table)

Answer 91

Question 92

Which cytokines are important for Tregs?

Answer 92

IL-10 and TGFβ

Question 93

BCR signaling (Figure)

Answer 93

Question 94

**MHC I Deficiency**

Answer 94

* Mutation: **_TAP_** * AR * Clinical features: Sinopulmonary infections, granulomatous skin lesions, and necrobiosis lipoidica * Laboratory: **CD8 lymphopenia, PBMC on flow cytometry lack MHC I** * Treatment: Treat pulmonary infections

Question 95

What cytokines induce IgA class switching?

Answer 95

**TGFβ and IL-5** Mucosal immunity, **IgA1** in serum and respiratory tract, **IgA2** in the lower GI tract.

Question 96

What receptor is involved with the inflammasome?

Answer 96

NODs

Question 97

T regulatory | (**Treg**)

Answer 97

Suppression immune response of other cells. Thymic emigrants that respond to self-Ag. Development → binding affinity between the cells and self-peptide MHC II (*T cell with intermediate binding*). **Treg:** * Express CD4, CD25 (IL-2Rα chain), and FoxP3 (master transcription factor). * Survival: IL-2 and TGFβ * Tolerance/regulation: IL-10 (targets MΦ and DC), TGFβ (inhibits lymphocytes and MΦ).

Question 98

IVIG causes a downregulation through __________ receptors.

Answer 98

**FcγRIIB**

Question 99

**MHC II Deficiency**

Answer 99

* Mutation: Several transcription factors required for MHC I expression (**_MHC2TA, RFX5, FRXAP, and FRXANK_**) * AR * Clinical features: Diarrhea, hepatosplenomegaly, transaminitis, sclerosing cholangitis (*C parvum*), pulmonary infections (PCP, encapsulated bacteria, Herpesviridae, and RSV), and meningitis * Laboratory: CD4 lymphopenia (reversed CD4: CD8), lack of HLA-DP, -DQ, -DR on lymphocytes, delayed hypersensitivity test, hypogammaglobulinemia, **absent germinal centers from LN** * Treatment: HSCT

Question 100

TCR signaling (Figure)

Answer 100

Question 101

RAS Associated Leukoproliferative Disorder (**RALD**)

Answer 101

Somatic mutation in **_NRAS or KRAS_**, primary features include *monocytosis, splenomegaly, normal DNTs.* There is some overlap with ALPS (however, remember that in ALPS, there is an increase [\>1.5%] α/β DNT cells)

Question 102

What is the main source of Factor D?

Answer 102

Adipose tissue

Question 103

**Bare Lymphocyte Syndromes** (Table)

Answer 103

Question 104

T-lymphocytes costimulation

Answer 104

Interaction between CD28 (T-cell) and both CB80/86, CD2, and CD58 → SLAM (signaling lymphocyte activation molecule) → activation/survival/stability/immune synapse SLAM has an ITSM that binds to SAP → links SLAM and Fyn (linked to CD3). **Key fact:** _Mutation in SAP_ ⇒ X-linked lymphoproliferative syndrome (**_XLPS_**)

Question 105

What has been associated with decreased galactosylation?

Answer 105

Inflammatory and infectious diseases (remember glycosylation of IgG is critical to maintaining structure/stability/function). Diseases associated with **_decreased galactosylation_** include RA, SLE, Chron'sdiseas, TB.

Question 106

What lipid mediators are considered to be anti-inflammatory and play a role in the resolution of allergic inflammation?

Answer 106

Lipoxin A4 Resolvin E1 Protectin D1

Question 107

What is the result of IFNγ receptor deficiency?

Answer 107

IFNγ receptor deficiency results in susceptibility to *Mycobacterium tuberculosis* and other intracellular bacteria.

Question 108

**Bim**

Answer 108

Self-Ag repeatedly recognized by a T lymphocyte without costimulation activate **Bim**, which is a **proapoptotic** member of the Bcl-2 protein family. Bim leads to cell apoptosis through the **mitochondrial** pathway.

Question 109

What is the first Ig produced after birth, the first to reach an adult level, and the first to be synthesized following antigenic stimulation?

Answer 109

**IgM**

Question 110

Immunoglobulin Isotypes | (Table)

Answer 110

Question 111

Antigen processing and MHC Presentation (*MHC II Pathway*)

Answer 111

**Key Fact:** HLA-DM is an intracellular protein involved in MHC IIantigen processing and does not present antigenic peptides nor is it a component of MHC II. Remember **_CLIP_**

Question 112

What cytokines are released by Th17 cells?

Answer 112

**IL-17 and IL-22**

Question 113

LAD type 1

Answer 113

CR3 or CR4 deficiency and is due to a rare mutation in the beta-chain (CD18) common to the CD11 or CD18 family of integrin molecules.

Question 114

**Hapten**

Answer 114

Small-molecule antigen, bound to a carrier protein, elicit the production of antibodies

Question 115

MHC (Constitutive and Cytokine)

Answer 115

MHC I: Most nucleated cells. _Cytokines:_ INFα, INFβ**,** and INFγ. MHC II: APC (dendritic cells, MΦ, and B cells). _APC can express both MHC I and II_. _Cytokines:_ INFγ. **Key Fact:** T cells only recognize antigens that are presented as part of the MHC complex ("MHC restriction"), which is restricted to peptides. *_Lipids, nucleic acids, and polysaccharides_* *are not presented by MHC molecules*.

Question 116

Conjugated vaccines

Answer 116

**Key Fact:** T-independent antigens linked to a carrier protein that triggers _T-dependent response and memory_. E.g., Prevnar-13, Hib, MCV4-Menactra, and Menveo.

Question 117

Epitope (Antigenic Determinant)

Answer 117

**Recognized by B lymphocytes:** * Linear determinants or tertiary structure in "native" conformation * Carbohydrates, amino acids (4 to 8 residues), nucleic acids, and phospholipids **Recognized by T lymphocytes:** * Linear determinants of amino acids only * Length limited by MHC binding cleft (MHC I [8 - 11 aa], MHC II 10-30 aa)

Question 118

What cytokines induce IgE class switching?

Answer 118

**IL-4 and IL-13** Allergic reaction, the **only** Ig to bind to mast cells

Question 119

MHC Genes

Answer 119

MHC I: HLA-A, -B, and -C MHC II: HLA-DP, -DQ, -DR

Question 120

Adjuvants

Answer 120

Molecules that are given in vaccines to enhance immune response (involves activation of the innate system leading to costimulatory expression and cytokine production). E.g., Alum, Freund's (BCG), Titermax (POP, POE). **Key Fact:** Adjuvants are necessary to achieve maximal adaptive immune response to a vaccine.

Question 121

MCH (structure)

Answer 121

_**MHC I****:**_ * **α chain:** *α₁ & α*₂ (_binding site_ for peptide [8 - 11 aa, intracellular]), *α*₃ (_binds **CD8**_) * β₂-microgobulin **_MHC II:_** * **α and β​** **chains:** *α₁ &* β1 (_binding site_ for peptide [10 - 30 aa, extracellular]), β2 (_binds **CD4**_), *α*₂

Question 122

What cytokines induce IgM class switching?

Answer 122

None Primary response (e.g., isohemagglutinin and RF)

Question 123

Complement Deficiencies (figure)

Answer 123

Question 124

Which cytokines increase eosinophil apoptosis?

Answer 124

**IL-4**

Question 125

Immunosuppressant cyclosporine binds to which molecule in the T-cell signaling pathway?

Answer 125

Cyclosporine binds to **_cycloph_****_ilin_** (also called immunophilins). The **_drug-protein complex inhibits calcineurin_** and therefore NFAT translocation to the nucleus.