Primary immunodeficiency Qs

What causes Chronic granulomatous disease (CGD)?

Due to mutations in 1 of 4 proteins forming NADPH (nicotinamide adenine dinucleotide phosphate) oxidase which produces hydrogen peroxide. (required for intracellular killing of phagocytosed organisms)

What B cell developmental outcome would a carrier female with normal X inactivated have?

arrested B cell development

In individuals with **XLA**, **B cells** are arrested at and fail to progress beyond which stage of development?

a. immature B cell stage

b. plasma-cell stage

c. pro-B cell stage

d. pre-B cell stage

d

Which of the following conditions is associated with **immune-complex disease**?

a. elevated bradykinin

b. oedema

c. anaemia

d. inflammation and tissue damage

e. C2a- angiodema

d

Which type(s) of gene defects are associated with primary immunodeficiency diseases?

a. dominant, recessive and X-linked

b. recessive an X-linked but not dominant

c. only recessive

d. only dominant

a

Which gene is responsible for **X-linked agammaglobulinemia** (**XLA**)?

a. BTK

b. RAG1

c. TAP

d. NOX1

a

Defects in the X-linked gene that encodes the common γ chain (γc) of a certain receptor are so severe that survival requires hematopoietic stem-cell transplantation. What is the name of this receptor?

a. cytokine receptor

b. IFNgamma receptor

c. CD3

d. Fc receptor

a

Inherited immunodeficiency diseases that manifest more frequently in males than in females are due to which type of defective **allele**?

a. dominant autosomal

b. recessive autosomal

c. recessive X-linked

c

What are individuals with **X-linked agammaglobulinemia** (**XLA**) unable to do?

a. kill bacteria in phagolysosomes

b. kill virus infected cells

c. produce antibodies

d. produce functional T cells

c

Women who are **carriers** of one nonfunctional copy of the BTK gene will have which one of the following?

a**.** mature B cells that have inactivated the same X chromosome

b. only half of the normal numbers of circulating B cells

c. sons who all lack mature B cells

d. XLA, because an insufficient amount of Bruton’s tyrosine kinase is made

a

HLA and KIR polymorphisms influence progression to AIDS. The scale shown in the accompanying figure represents relative hazard, which measures the speed of progression to AIDS, with 1.0 being faster than 0.

The HLA-B\*27 and HLA-B\*57 allotypes (represented by B27 and B57, respectively) share the Bw4 epitope, the ligand for the NK-cell receptor KIR3DL1 (3DL1). KIR3DL1 can be highly expressed (3DL1h) or weakly expressed (3DL1l). Combinations of Bw4+ HLA-B and KIR3DL1/S1 genes are associated with different rates of progression to AIDS.

People called elite controllers and viremic controllers are likely to benefit the most from the presence of which of the following?

a. Bw4+ HLA-B\*57

b. Bw4+ HLA-B\*57 and KIR3DL1h

c. Bw4+ HLA-B\*27 and KIR3DL1h

d. a complete lack of Bw4 epitope on the HLA-B allotype

b

Interferon-γ (IFN-γ) is the main cytokine that activates macrophages. The IFN-γ receptor is a dimer of the IFNγR1 and IFNγR2 polypeptides, which associate with the JAK1 and JAK2 tyrosine kinases, respectively. Dominant and recessive mutations in the gene for IFNγR1 have been found in individuals suffering from persistent mycobacterial infections. Which of the following statements accurately describes the effect of mutations in the IFN-γ receptor?

**a.** Patients with two recessive defective IFNγR1 alleles express neither IFNγR1 nor IFNγR2 on the cell surface of monocytes and macrophages.

b. Mutations in the recessive IFNγR1 alleles prevent any cell surface expression of IFNγR1.

**c.** Individuals with one dominant defective IFNγR1 allele have more-severe disease than patients with two recessive IFNγR1 alleles.

d. Signaling through the IFN-γ receptor is not very important for the functions of macrophages.

b

When does the loss of an immune-system gene associated with an inherited **immunodeficiency disease** usually NOT pose a serious consequence?

**a.** if a compensatory function is provided by another member of the multigene family

b. if the loss or defect is in the receptor genes, such as the one for CCR5, which code for receptors exploited by pathogens like HIV

**c.** f the defect arises after a well-established circulating lymphocyte pool has been produced

d. If gene reversion converts the defective gene to the normal variant early in embryogenesis

a

When is the **autoimmune disease** **hereditary angioedema** (**HAE**) manifested?

**a.** when both C1INH alleles are nonfunctional

b. when C1INH is overexpressed

**c.** when one C1INH allele is nonfunctional, but the other is unaffected

c

Which function is affected by defects in the CHS1 gene that is present in individuals with **Chédiak–Higashi syndrome** (CHS)?

a. the respiratory burst

b. chemotaxis

**c.** opsonization

d. vesicle fusion

d

Which of the following is NOT observed in **leukocyte adhesion deficiency**?

**a.** impaired migration of monocytes and neutrophils to infected tissues

b. defective respiratory burst

**c.** defective uptake of opsonized bacteria

d. susceptibility to encapsulated bacteria

b

A deficiency of which one of the following causes a selective absence of **CD8** T cells?

**a.** RAG proteins

b. SH2D1A protein

c. TAP transporters

**d.** purine nucleoside phosphorylase (PNP)

e. Wiskott–Aldrich syndrome protein (WASP)

c

Which of the following is true of the disease caused by **adenosine deaminase** (ADA) deficiency?

a. It is a recessive X-linked disorder that affects more males than females.

b. It results from the accumulation of nucleotide metabolites that are especially toxic to T cells.

c. It is characterized by the inability to deliver intracellular signals in T cells.

d. It interferes with cognate interactions between T cells and B cells.

b

Which one of the following statements accurately describes an immune condition associated with **severe combined immune deficiency** (**SCID**)?

a. Physical barriers of innate immunity are compromised.

b. All complement pathways are inhibited.

c. Neither antibody nor T-cell responses are made.

d. Both innate and adaptive immunity are ineffective.

c

Intravenous administration of which of the following can cure **neutropenia** in individuals with **X-linked hyper-IgM syndrome**?

a**.** granulocyte–macrophage colony-stimulating factor (GM-CSF)

b. antibiotics

c. immunoglobulin

d. CD40 ligand

a

Which pathogen poses the biggest threat to individuals with **XLA**?

a. an intestinal helminth

b. an opportunistic fungus

c. an extracellular protozoan parasite

d. an enveloped virus

e. a pyogenic bacterium

e

Which of the following syndromes is caused by a defective protein involved in cytoskeletal reorganization that is needed for **cytokine** delivery and the formation of conjugate pairs?

a. Wiskott–Aldrich syndrome (WAS)

b. Janus 3 kinase (JAK3) deficiency

c. Omenn syndrome

d. Chédiak–Higashi syndrome (CHS)

a

Which cells fail to develop in individuals with a homozygous defect in CIITA?

**a.** platelets

b. B cells

c. NK cells

**d.** CD4 T cells

e. CD8 T cells

d

Which of the following syndromes are associated with the inefficient killing of ingested pathogens?

Correct Answer(s)

a. myeloperoxidase deficiency (MPOD)

b. hereditary angioedema (HAE)

c. glucose-6-phosphate dehydrogenase (G6PD) deficiency

d. paroxysmal nocturnal hemoglobinuria (PNH)

e. chronic granulomatous disease (CGD)

f. Chédiak–Higashi syndrome (CHS)

g. leukocyte adhesion deficiency (LAD)

a, c, e

Select all the statements that are true regarding IFN-γ receptor deficiency.

\
a. IFNγR2 cannot function in the absence of IFNγR1.

b. Patients with two recessive defective IFNγR1 alleles express neither IFNγR1 nor IFNγR2 on the cell surfaces of monocytes and macrophages.

c. In IFN-γ receptor deficiency, macrophages infected with Mycobacterium tuberculosis cannot be activated in either innate or adaptive immune responses.

d. Dominant mutant forms of IFNγR1 are less abundant at the cell surface than normal forms.

e. Patients with two recessive defective IFNγR1 alleles exhibit more severe disease at an earlier age than patients with one dominant defective IFNγR1 allele.

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a, c, e

Which of the following are observed in individuals who do not produce functional CD40 ligand?

a. an increased susceptibility to pyogenic bacterial infections

b. high levels of granulocyte–macrophage colony-stimulating factor (GM-CSF)

c. the absence of germinal centers in secondary lymphoid tissues

d. low amounts of all isotypes of antibody

e. a state called neutropenia

a, c, e

What do CR3, CR4, and LFA-1 have in common?

a. They are all leukocyte integrins.

b. They all contain CD18.

c. They are all complement receptors.

d. They are all serpins.

a, b

Which the following statements regarding an IL-12 receptor deficiency are correct?

a. Signaling through the IL-12 receptor of NK cells stimulates the production of IFN-γ.

b. Innate, but not adaptive, immune responses to intracellular bacteria are intact in patients with an IL-12 receptor deficiency.

c. Individuals with an IL-12 receptor deficiency are predisposed to infections caused by mycobacteria.

d. Signaling through the IL-12 receptor of naive CD4 T cells induces their differentiation into TH2 cells.

 

a, c

Which of the following are required for signaling by the IFN-γ receptor?

a. JAK1 and JAK2

b. STAT1

c. MyD88

d. NFκB

a, b

What will a normal male have as the correct B-cell development outcome?

Functional B cells

What B-cell developmental outcome will a carrier female with defective X inactivated have?

Functional B cells

What B cell developmental outcome would an XLA male have?

arrested B cell development

MHC class II deficiency is associated with which homozygous defect?

a. CIITA

b. either of RAG proteins

c. either of TAP peptide transporters

d. any of the components of RFX

a, d

Which of the following holds true if a woman carries one defective Bruton’s tyrosine kinase (BTK) allele?

a. She has no functional B cells and is therefore unable to produce antibodies.

b. She will produce IgM, but not IgG or IgA, antibodies.

c. If her husband has a normal form of BTK, then 50% of her daughters will not be able to produce antibodies.

d. Her B cells will exhibit nonrandom X-chromosome inactivation.

e. She requires monthly injections of gamma globulin to prevent bronchiectasis.

d

Mutations that lead to a nonfunctional NADPH oxidase system are associated with _____.

a. neutropenia

b. chronic granulomatous disease

c. immune-complex disease

d. opportunistic viral infections

e. Chédiak–Higashi syndrome

b

Which primary immunodeficiency results in recurrent respiratory/genitourinary infections?

Selective IgA deficiency

What 3 main B cell markers are used for enumerate B cells by immunophenotyping?

CD19, CD20, CD22

What type of inheritance is **Chediak-Higashi disease?**

Autosomal recessive in *CHS*

Proportion of CGD that is X-linked?

70%

Proportion of autosomal recessive genes in CGD?

30%

Nitroblue Tetrazolium Test in cells from a patient with X-linked chronic granulomatous disease

completely absent

The mother of the patient is a carrier of the mutation and has what NBT result?

both NBT-positive and -negative cell populations

SCID suffer with

Recurrent viral, bacterial, fungal, protozoan infections due to **lymphopenia**-prolonged diarrhoea from gastrointestinal infections, pneumonia (*Pneumocystis jirovecii*), skin/mouth infections (*Candida albicans*)

Defects in AIRE

Autoimmune polyendocrine syndrome-1

Infections of those with defects in AIRE

*Candida albicans*

Defects in Foxp3

Immune dysreulation, polyendocrineopathy, enteropathy and X-linked IPEX

Deletion of what causes digeorge syndome?

TBX1 gene: transcription factor is highly expressed during  the phases of embryonic development when the facial structures, heart, tyroid, parathyroid, and thymus are forming

Deficiency in C1, C2, C4

Immune-complex disease

Deficiency in C3

Susceptibility to encapsulated bacteria

Deficiency in C5-C9

Susceptibility to Neisseria

Deficiency in Factor D, properdin (factor P)

Susceptibility to encapsulated bacteria and Neisseria but no immune-complex disease

What deficiency has similar effects to deficiency in C3?

Factor I

Deficiency in DAF, CD59

Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria

Deficiency in C1INH

Hereditary angioedema (HAE)

Inheritance of hereditary angioedema

autosomal dominant

Characterizing the condition of HAE

bouts of subepithelial swelling of the face, larynx, and abdomen. The swollen larynx sometimes causes death by suffocation.

Which condition involves the impairment of platelets and lymphocytes

Wiskott–Aldrich syndrome (WAS),

CHS1

gene encoding the lysosomal trafficking protein

Leukocyte adhesion deficiency (LAD) defect in

CD18 gene

Clinical effect of LAD

Widespread infection with encapsulated bacteria

What 3 disorders have the same functional effect: Defective respiratory burst Phagocytes unable to kill pathogens?

Chronic granulomatous disease, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, Myeloperoxidase deficiency (MPOD)

What is deficient in Myeloperoxidase deficiency (MPOD)?

Myeloperoxidase

What is deficient in G6PD?

Glucose-6-phosphate dehydrogenase

What in addition to chronic bacterial and fungal infections are CGD patients susceptible to?

granuloma

In addition to chronic bacterial and fungal infections what else is effected in G6PD?

Some infections induce anemia

What is the clinical effect of MPOD?

Chronic bacterial and fungal infections

What is deficient in Chédiak-Higashi syndrome?

Lysosomal trafficking regulator protein

What is the functional defect of a defect in Lysosomal trafficking regulator protein in CHS patients?

Defective fusion of endosomes and lysosomes Defective phagocytosis

What is the clinical effect of CHS?

Recurrent and persistent bacterial infections, granulomas Damaging effects to many organs

Twelve-year-old Morgan Boyd had a 7-month history of several episodes of sudden onset of swelling of her tongue, lips, and eyes. These recurrences lasted 1–3 days before subsiding without medical intervention. Her older brother, Stephen, had had a similar problem when he was 16 years old. The edema was not itchy and there was no urticaria. Morgan did not experience airway obstruction or abdominal discomfort during any of her episodes. She was not taking any medications and did not have any drug allergies. A diagnosis of hereditary angioedema (HAE) was made on the basis of (1) blood measurements of key complement components after remission and again during a subsequent attack of angioedema, and (2) C1INH quantitative and qualitative tests. Which of the following complement proteins would be well below normal range in Morgan in both of her blood tests?

a. C1q

b. C3

c. C4

d. C5

e. C9

c

Loss-of-function mutations in the common γ chain (γc) gene are particularly damaging to the immune system because _____. (Select all that apply.)

a. homozygotes and heterozygotes fail to make sufficient γc protein for lymphocyte activation

b. they can result in severe combined immune deficiency (SCID)

c. T-cell dependent and T-cell independent B-cell responses are inhibited

d. multiple cytokine receptors cannot signal

e. MHC class II genes are unable to be expressed

b, d

Type of SCID with B+, nk+

IL-7Ralpha (5%)

SCID T-/B+/NK-

JAK3 (10%)

SCID T-/B-/NK+

RAG1, RAG-2 (15%)

SCID T-/B-/NK-

ADA (10%)

SCID T-/B-/NK- and causes reticular dysgenesis

AK2 (4%)

SCID T-/B-/NK+

Artemis (15%)

CD3E, CD3DELTA, CD45, CORO1A (1%, 1%)

T-/B+/NK+

SCID T-/B+NK-

Gamma c chain (40%)

SCID T-/B+ /NK- X-linked

X-SCID

Digeorge gene

deletion of TBX1

TBX1

this transcription factor is highly expressed during  the phases of embryonic development when the facial structures, heart, tyroid, parathyroid, and thymus are forming

DiGeorge FISH

22q11.2 del

t-/b+/nk+

Digeorge

Why is there a T cell deficiency in DiGeorge syndrome?

Underdeveloped thymus

DiGeorge (Velocardiofacial) syndrome: Treatment total aplasia

Total aplasia is rare

* lGrafting neonatal thymus restores immune function (immunocompetence)
* lAntibody administration (passive immunity)

\

DiGeorge (Velocardiofacial) syndrome: Treatment partial aplasia

* Partial hypoplasia is more common
* lT-cells increase from 6% at birth to \~30% of total circulating lymphocytes at 1 year (compared with 60-70% in normal  1 year olds)
* lNormal antibody responses
* lNo immunological intervention required

Which of these is not a consequence of a lack of thymus?


1. No T cells
2. Sparsely populated lymphoid tissue (thymus-dependent areas)
3. Poorly developed lymphoid follicles
4. No cell-mediated immunity
5. Complete abnormal antibody response
6. Subnormal antibody response

5

Primary T cell deficiency: DiGeorge (Velocardiofacial) syndrome

Developmental disorder affecting thymus (failure of the thymus to develop properly from the third and fourth pharyngeal pouches).

Other features DiGeorge

lLack parathyroid

lSevere heart abnormalities

lImmunodeficiency

lmoderate learning difficulties

lFish-like mouth

ldown-slanting palpebral fissures

¡1 in 4,000 births

Diagnosis of Primary T-cell deficiency

¡Hypo- or unreactive in skin tests to tuberculin, *Candida* and mumps

¡Phytohaemagluttin activation of T-lymphocytes

Enumeration of T cells by immunophenotyping-CD3 (TCR on T cells), CD4 (MHC class II receptor on T cells) and CD8 (MHC class I receptor on T cells)

Patients with no T-cells or poor T-cell function are vulnerable

lOpportunistic infection



lPoor humoral immunity



lAllergies



lLymphoid malignancies



lAutoimmune diseases (inefficient negative selection in thymus, failure to generate T regulatory cells)

SCID treatment

¡If B cells affected, intravenous immunonglobulins are given every 3-4 weeks



¡Gene therapy when a matched transplant is not available. Mainly with ADA-SCID, more recently **γ**c chain cytokine receptor gene.



¡Haemopoietic stem cell transplant (bone marrow, peripheral blood, cord blood) is treatment of choice, if a suitable match is available



¡Patients with adenosine deaminase deficiency, ADA SCID, without a suitable HSCT match, receive weekly ADA enzyme replacement therapy

RAG1/2-recombination activating gene 1/2 –important genes which control the recombination of the v,d, and j segments of the Ig and T cell receptor loci,.  Mutations of these genes prevent

production of any mature lymphocytes.

Which genetic defect leads to defective cytokine signalling?

Gamma c cytokine, IL7RA, JAK-3

Which genetic defect leads to no TCR or Ig gene rearrangement → no mature lymphocytes?

RAG1, RAG2, ArtemisW

What defect leads to a toxic metabolite in T and B cells?

ADA

What blocks differentiation of early myeloid and lymphoid precursosrs?

AK2

most important receptorfor lymphocyte differentiation

il-7ra

TRANSDUCES gamma chain signal

JAK3