Immunodeficiency syndromes

Question 1

IFNg deficiency

Answer 1

Presdisposition to early TB and atypical mycobacterial infections. Often disseminated, miliary.

Question 2

IL-12 deficiency

Answer 2

Broadly imparied Th1-mediated immunity, macrophage-mediated immunity, and antimycobacterial immunity (poor granuloma formers)

Predisposed to viral, fungal, and mycobacterial infections

Question 3

Job syndrome

Answer 3

Aka, autosomal dominant hyper IgE syndrome

Caused by STAT3 LoF, resulting in Th17 deficiency and atopic features. IgE is elevated, all other Igs are in the normal range. Peripheral eosinophilia often present.

Th17 deficiency results in poor persistent PMN response, often manifesting as poor response to cutaneous fungal infections and abscesses without pus.

Other features: Delayed shedding of primary teeth, frequent fractures, joint hyperextensibility

Question 4

Paradoxically, patients with CVID often develop. . .

Answer 4

. . . autoimmunity

Question 5

Ways to arrive at secondary immunodeficiency

Answer 5

• Systemic disorders of metabolism (T2DM, cirrhosis, CKD)
• Hypoproteinemia-associated hypogammaglobulinemia (protein malnutrition, nephrosis, gastrosis, massive protein loss loss of skin integrity in burns or severe eczema)
• Hematopoietic system insult (toxins/chemotherapy, cigarette smoke, viral, post-viral)

Question 6

NEMO syndrome

Answer 6

NF-κB essential modualtor defect syndrome

Other features: Conical teeth, ectodermal dysplasia

Question 7

Ataxia-telangiectasia

Answer 7

ATM gene mutation

Selective IgA deficiency

Other features: Cerebellar degeneration, telangiectasias

Question 8

Schwachman-Bodian-Diamond syndrome

Answer 8

Immunodeficiency manifesting as primarily as neutropenia

Other features: childhood myelodysplasia, pectum carinatum, skeletal dysostosis, exocrine pancreatic insufficiency

Question 9

Leukocyte adhesion deficiency

Answer 9

Beta-2 integrin defect, impairs neutrophil recruitment and neutrophil margination

Characterized by recurrent bacterial infections, cutaneous fungal infections, elevated circulating PMNs at baseline. Infections/abscesses without pus.

Other features: Delayed shedding of umbilical cord (>2 weeks).

Question 10

DDx for recurrent respiratory infection by encapsulated organisms

Answer 10

1. Anti-polysaccharide antibody production (T-cell-independent B cell function)
2. Neutrophil functional defect
3. Early complement defect

Question 11

Level I lab testing for suspeted primary antibody deficiency

Answer 11

CBC w/ diff

Complement studies (CH50, C3, C4, MBL)

ESR

IgM, IgG, IgA, IgE levels

Question 12

Autosomal agammaglobulinemias

Answer 12

Due to failure of expression of the pre-BCR and subsequent failure of B cell selection

Can be due to loss of function in: TCF3 (aka E2A) or PIK3R1, as well as some less common genes.

Treatment is the same as for X-linked agammaglublinemia (BTK deficiency).

Question 13

Hyper-IgM syndrome

Answer 13

Due to failure of class switching/B cell costimulation

Classically CD40 or CD40L deficiency, but may also be activation-induced cytosine deaminase (AID) or uracil-DNA glycosylase (UNG).

Among the classical disorders (CD40-CD154 axis), lymphoid hyperplasia and splenomegaly are common findings, and germinal centers are absent.

AUD or UNG-type Hyper-IgM patients may present with biopsy showing giant germinal centers filled with highly proliferative B cells.

Question 14

Basic criteria for a CVID-family disorder

Answer 14

1. Patient at least 4 years old
2. Deficient production of at least two classes of antibody
3. Response of these classes of antibody to vaccination are depressed or absent

Question 15

CD27

Answer 15

TNFSF receptor

Cell surface marker of normal memory B cells

Question 16

Noncaseating granulomas in CVID

Answer 16

Generally more characteristic of sarcoidosis, but also occur in up to 20% of CVID patients.

Question 17

CVID genes

Answer 17

• Non-typed CVID: MHC haplotype risk factors
• CVID1: ICOS deficiency, AR
• CVID2: TACI deficiency, AR or AD
• CVID3: CD19 deficiency, AR
• CVID4: BAFF-R deficiency, AR
• CVID5: CD20 deficiency, AR
• CVID6: CD81 deficiency, AR
• CVID7: CD21 deficiency, AR
• CVID8: LRBA deficiency, AR
• CVID9: PKCδ deficiency, AR
• CVID10: NF-κB2 deficiency, AD
• CVID11: IL-21 deficiency, AR
• CVID12: NF-κB1 deficiency, AD

Question 18

B-cell coreceptor complex disorders / CVID subtypes

Answer 18

The BCR coreceptor complex is made up of CD19, CD21, and CD81.

CD21 is also known as CR2, a C3b receptor that potently increases the effects of BCR activation. This phenomenon is referred to as “B cell costimulation.”

Deficiencies in all three of these components can cause CVID.

Question 19

BAFF-TACI axis and CVID

Answer 19

BAFF and APRIL are two TNFSF members which bind to the receptors BCMA and TACI on B cells and T cells. BAFF-R, a third receptor for these ligands, is expressed exclusively on B cells.

These ligands and receptors play important roles in B cell maturation and homeostasis, including being important for heavy chain class switching.

Mutations in TACI and BAFF-R have been found to produce CVID.

Question 20

CD20 and CVID

Answer 20

CD20 has no known ligand, but appears to be important for B cell survival and maturation, as well as for T-cell independent B cell responses.

It is believed to act as a Ca channel.

It is present from late pro-B cells through memory B cells, but is not present on plasma cells.

Question 21

ICOS and CVID

Answer 21

ICOS is a T_FH cell protein that is important for germinal center formation, terminal B cell differentiation, and immune tolerance.

Patients with ICOS deficiency have low to absent B cells and have varying degrees of T cell dysfunction. It often presents with recurrent respiratory tract infections and autoimmune complications.

Loss of function in ICOS causes CVID type 1.

Question 22

The LRBA-CTLA-4 axis and CVID

Answer 22

LRBA is a cytosolic protein that functions in vesicle trafficking, autophagy, and cell survival. It is expressed in all cells, but has higher expression in immune effector cells.

LRBA is important for CTLA-4 surface expression.

LRBA deficiency results in CVID type 8, which often involves associated autoimmunity.

Question 23

PKCδ deficiency and CVID

Answer 23

PCKδ is a signaling molecule downstream of BTK, relevant in B cell survival, proliferation, and tolerance.

The phenotype of PCKδ deficiency is variable, with some patients having a CVID-like presentation and some having an autoimmune/SLE-type picture.

Question 24

NF-κB1 and 2 and CVID

Answer 24

Both NF-κB family proteins are downstream of several important B cell receptors (ICOS, TACI, BCMA, BAFF-R), and NF-κB1 is also downstream of the TCR.

Both are associated with autoimmunity and immunodeficiency w/ panhypogammaglobulinemia. NF-κB1 loss of function is associated with more profound immunodeficiency while NF-κB2 loss of function is often associated with pituitary autoimmunity (~50% of cases).

Question 25

PI3K pathway and CVID

Answer 25

PIK3CD GoF mutations have been found to lead to autonomous PI3K activity.

PIK3R1 encodes p85 alpha, a regulatory subunit of PI3Kδ. Loss of function is haploinsufficient and also results in overactive PI3K signaling.

Both of these result in a CVID-like syndrome called activated PI3Kδ syndrome (APDS).

Question 26

Kabuki syndrome

Answer 26

Caused by mutations in histone demethylases KMT2D or KDM6A.

Results in a CVID-like immunodeficiency plus syndromic features (abnormal fascies, short stature, cardiac abnormalities, variable intellectual disability)

Question 27

IFNγ circuit disorders

Answer 27

IFNγR1 and 2 deficiency, STAT1 deficiency, IL12B (encodesthe p40 subunit of IL-12 and IL-23, the IFNγ-induced cytokines), NEMO (modulator of NF-kB, involved in IL-12 induction), IRF8 (IFNγ-induced transcription factor, regulates IL12 expression), TYK2 (tyrosine kinase that is recruited to IL12 receptor, like JAK kinases), ISG15 (IFNγ-inducing molecule that enhances IL12 signaling at IL-12R), CYBB aka p91phox.

All result in strong presdisposition to mycobacterial disease. Complete IFNγR deficiencies also strongly presdispose to viral disease. STAT1 deficiency also knocks out alpha and beta interferons, resulting in profound viral immunodeficiency. Connects to PHOX and the CGD disease pathway.

For img, see ch36 fig 36.1

Question 28

STAT1 deficiency

Answer 28

Extremely vulnerable to Type 1 immunologic insults, especially viruses (even live attenuated will kill these people)

Question 29

RIPK1 mutant phenotypes

Answer 29

Biallelic deletion: SCID + IBD

Death domain missense mutations: IBD

Non-cleavable RIPK1: ie, RIPK1 that cannot be cleaved by caspase-8 (D324 mutation). Autoinflammatory disease characterized by fevers, lymphadenopathy.