Immuno- Primary immune deficiencies Flashcards by Lottie Barot

How are T cells selected in the thymus?

Depends on their affinity for HLA

low affinity = not selected
high affinity = negative selection due to auto reactivity
intermediate affinity = positive selection

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How do lymphoid progenitors become CD4 or CD8?

Lymphoid progenitors express both CD4 and 8. If they bind with intermediate affinity to MHCII –> become CD4
Bind with intermediate affinity to MHCI –> become CD8

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2 ways in which CD8 cells kill cells directly?

Perforin + granzymes

Expression of Fas

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CD4+CD25+Foxp3+ ?

Treg cells

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Th17 cells - what do they do?

Aid neutrophil recruitment

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Describe DiGeorge syndrome

Mnemonic for clinical features?
B and T cell levels?
Does immunity change with age?

2q11.2 deletion syndrome
CATCH - 22
Cardiac defects, Abnormal face (high forehead, low set ears), Thymic aplasia, Cleft palate, Hypocalcemia/hypoPTH, 22q11.2 deletion

B cells normal. T cells low (due to thymic aplasia)

Homeostatic proliferation with age –> immune function improves!

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V low CD4 count
Normal CD8 cell count
Low IgG, low IgA

Bare lymphocyte syndrome Type 2

due to absent expression of MHC class II –> no CD4 cells develop from lymphoid progenitors!

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4 Hx features of bare lymphocyte syndrome

Failure to thrive at 3 months
Infections
Prone to sclerosing cholangitis
FHx of infant death

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2 types of disorders of T-cell effector function + egs.

Cytokine/receptor deficiency (IL12 and IFNgamma)

Failure to communicate with B cells = HyperIgM syndrome (where T cells fail to express CD40L)

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Most common form of SCID? cause? how does it cause any problems?

X-linked SCID
Mutation of gamma chain of IL2-RECEPTOR

–> inability to respond to cytokines involved in lymphoid development

-> arrest of T +NK cell development
-> increased immature B-cells

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Phenotype of SCID?

Levels in X-linked SCID
T cells? B-cells? Thymus?

Unwell at 3 months + failure to thrive, persistent diarrhoea, bare infections

Vv low T-cells
Normal/raised B cells
Poorly developed thymus

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T-cell deficiencies increases your risk of…?

INTRACELLULAR pathogens
- TB, salmonella

Viral - CMV
Fungal - PCP

early MALIGNANCYA

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Ix for suspected lymphocyte deficiencies?

WCC
Lymphocyte subsets
serum Ig
Functional tests
HIV

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5 avenues of Mx for T-cell deficiencies

Aggressive prophylaxis/Tx of infection
SC transplantation
Ig replacement
Enzyme replacement for ADA SCID
Experimental - thymus transplant in DiGeorge, gene therapy

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How do B-cells produce different classes of Ig?

Immature B-cells produce IgM.

Once activated by signalling via cytokine receptors by T-helper cells, they switch to producing IgA/E/G

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Which type of T-cell deficiency will affect antibodies?

CD4 T-helper cells

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Most severe B-cell deficiency? Aetiology? Ix results? Presentation?

Bruton's X-linked hypogammaglobulinaemia
Due to BTK gene defect
Arrest of B-cell maturation 
- Low B-cells and all Igs
- recurrent infections in childhood (bacterial, enterovirus)

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B-cell deficiency where class switch is affected?
Aetiology?
Presentation - any specific pathogens?

HyperIgM syndrome
CD40L gene (Chr Xq26) is mutated on T-helper cells --> B-cells aren't activated to class switch

Boys - present in 1st few years of life: recurrent bacterial infections
esp PCP
Also autoimmunity + malignancy - esp NHL

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Ix results in HyperIgM syndrome

High IgM. Low IgA/E/G

Normal B and T cells.

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Heterogenous group of disorders where disease mechanism is unknown
Low IgG, IgA and IgG

Common variable immune deficiency

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3 main clinical features of common variable immune deficiency w egs

V severe recurrent bacterial infections (w end organ damage)
- bronchiectasis, sinusitis, GI infection
Autoimmune disease
Granulomatous disease

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Results on electrophoresis in Bruton’s

No signal for Gamma

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Antibody/B-cell deficiencies: susceptible to what kind of infections

Bacterial!!!!
Toxins - tetanus, diphtheria
Entroviruses

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What measurement is a surrogate marker for CD4 T-helper cell function

IgG

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Mx of B-cell deficiencies?

Aggressive Tx of infection Ig replacement every 3 weeks BM transplant

Specific management of IgA deficiency

Immunisation

Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE - which B-cell deficiency?

Common variable immunodeficiency (the combo of immunodeficiency + autoimmunity)

Recurrent bacterial infection in a child, episode of PCP, high IgM, absent IgA and IgG...which B-cell deficiency?

X-linked hyper IgM

1 year old boy with recurrent bacterial infections | CD4 and CD8 T cells normal. B cells absent. IgG, IgA and IgM absent

Bruton's X-linked hypogammaglobulinaemia BTK gene mutation --> inability for B cells to mature

Recurrent respiratory tract infections, absent IgA, normal IgM and IgG

IgA deficiency

Severe recurrent infections from 3 months old. CD4 and CD8 T cells and NK cells absent. B cells present. Igs normal. Normal facial features and cardiac echo. Which lymphocyte deficiency is this?

X-linked SCID Gamma chain of IL2 receptor is defected. Inability to respond to cytokines --> early arrest of T cell and NK cell development

Young adult with chronic infection with mycobacterium marinum. Which lymphocyte deficiency is this?

IFNgamma or IL12 deficiency or defect of their receptors

Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG - which lymphocyte deficiency is this?

DiGeorge syndrome ``` Thymic aplasia --> low T cells. Low T cells --> inability for B-cells to class switch --> low IgA and IgG ```

6 month baby with 2 recent serious bacterial infections, T cells present but only CD8+. B cells present. IgM present but IgG low. Which lymphocyte deficiency is this?

Bare lymphocyte syndrome type II Deficiency of functional MHC class II, therefore no development of CD4 T cells.

Recurrent infections with high neutrophil count on FBC but no abscess formation Which phagocyte deficiency is this?

Leukocyte adhesion deficiency

Recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test Which phagocyte deficiency is this?

Chronic granulomatous disease Deficient in a component of NADPH oxidase --> inability to kill via oxidative killing.

Recurrent infections with no neutrophils on FBC | Which phagocyte deficiency is this?

Kostmann syndrome

Infection with atypical mycobacterium. Normal FBC. What phagocyte deficiency is this?

IFN gamma receptor deficiency

Meningococcal meningitis with FHx of sibling dying of same condition aged 6. Which complement deficiency is this: C7? C3? MBL? C1q?

C7 - terminal common pathway defect --> inability to lyse encapsulated bacteria

Membranoproliferative nephritis and bacterial infections Which complement deficiency is this? C7? C3 with presence of a nephritic factor? MBL? C1q?

C3 deficiency with presence of a nephritic factor (an autoantibody against parts of complement pathway which stabilises C3 convertases)

Severe childhood onset SLE with normal levels of C3 and C4. Which complement deficiency is this? C7? C3 with presence of a nephritic factor? MBL? C1q?

C1q: deficiency of early classical pathway. Immune complexes fail to activate the complement pathway + increased load of self-antigens esp against nuclear components.

Recurrent infections when receiving chemotherapy but previously well. Which complement deficiency is this? C7? C3 with presence of a nephritic factor? MBL? C1q?

MBL deficiency - this deficiency is rarely problematic unless there is a coexisting cause for immune impairment

Most severe primary immune deficiency ? Cause? Management?

Reticular dysgenesis - AK2 mutation --> failure of cells to differentiate along Myeloid + Lymphoid lineage - Mx: fatal without urgent BM transplantation

Episodic neutropenia every 4-6 weeks with periods of good health? What is this condition? What is the cause?

Cyclic neutropenia | Mutation in ELA-2 (neutrophil elastase)

What is deficient in Leukocyte adhesion deficiency?

CD18 deficiency - this usually is expressed by neutrophils and binds to endothelial cells for adhesion + transmigration

3 features of leukocyte adhesion deficiency

1. Normal neutrophil count on FBC 2. Absence of pus and abscess 3. Delayed umbilical cord separation

Name of disease where oxidative killing mechanism is impaired? How does this happen?

Chronic granulomatous disease Deficiency of a component in NADPH oxidase

Which bacterial infections are patients with CGD prone to?

PLACESS | Pseudomonas, listeria, aspergillus, Candida, E Coli, staph aureus, serratia

2 Ix which are abnormal in CGD?

NBT and DHR

Which primary immune deficiency is associated with mycobacterial infection? In this deficiency, what are its unable to form?

IFNgamma/IL12 or their receptor deficiency These are required for activation of oxidative killing Inability to form GRANULOMAS

Ix for suspected phagocyte deficiencies?

FBC Leukocyte adhesion markers NBT or DHR (for oxidative killing in CGD) Pus/abscess formation

In NK deficiency, what is a patient susceptible to? Mx?

VIRAL infections: HSV, VZV, EBV, CMV, HPV prophylactic antivirals

2 types of NK cell deficiency? What are their causes?

Classical = the absence of NK cells. - GATA2 + MCM4 Functional = abnormal function - FCGR3A

The classical complement pathway - what is it activated by? | Classical pathway deficiency is associated with....?

Activated by immune complexes - associated with SLE = due to increased load of self-antigens

Secondary deficiency of the classical complement pathway - what is it?!

Active SLE --> persistent production and consumption of complement

Which complement deficiency is quite common? when is it a problem?

MBL deficiency - only problematic with co-existing cause of immunodeficiency eg chemotherapy

2 things which patients with C3 deficiency are susceptible to?

1. Infection with encapsulated bacteria (meningococcus, strep, haemophilia) 2. connective tissue disesase

WTF is secondary C3 deficiency Assoc with?

Nephritic factors present : they are directed against parts of the complement pathway. They STABILISE C3 CONVERTASES --> increased C3 consumption Associated with glomerulonephritis

4 Ix used to determine complement deficiencies?

C3, C4, CH50, AP50

SLE is associated with deficiencies in which components of the complement pathway?

C1,2, and 4