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Year 5 Immunology > 6: Immune Deficiencies > Flashcards

6: Immune Deficiencies Flashcards

1
Q

Phagocyte deficiencies result in infections of the (2)

A

recurrent skin/mouth

  • bacterial → S. aureus, enteric bacteria
  • fungal → candida, aspergillus fumigatus and flavus

mycobacterial infection

  • MTB
  • Atypical mycobacterium
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2
Q

How do we treat phagocyte deficiencies?

A

Definitive therapy:

  • HSCT (replaced defective population)
  • specific tx of CGD (IFN-y) therapy

Infection prophylaxis (antibiotics, anti-fungals)

oral/IV abx as needed

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3
Q

What are features of NK cels

A

Inhibitory receptors recognise self-HLA → prevent inappropriate activation to normal self

Activator receptors (inc. natural cytotoxicity receptors) recognise heparan sulphate proteoglycans

  • Cytotoxicity
  • Cytokine secretion
  • Contact-dependent regulation
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4
Q

Deficiencies of NK cells lead to

A

virus infections:

  • HHV infections = HSV½, VZV, EBC, CMV
  • HPV infection

tx:

  • prophylactic aciclovir/ganciclovir
  • HSCT (severe phenotypes)
  • Cytokines (IFN-a to stimulate NK cytotoxic function)
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5
Q

Give 3 conditions for failure of neutrophil differentiation

A

Reticular dysgenesis

Congenital neutropenia (Kostmann)

Cylic neutropenia

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6
Q

What is reticular dysgenesis?

A

failure of stem cells to differentiate along myeloid or lymphoid lineage

AR, severe SCID

mutation in adenylate kinase 2 (AK2, mitochondrial energy metabolism enzyme)

low B/T cell numbers as SCID (differentiate from Kostmann’s)

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7
Q

What is Kostmann syndrome (failure of neutrophil maturation)?

A

AR, severe congenital neutropenia

classical form due to mutation in HCLS1-associated protein X-1 (HAX1)

NO NEUTROPHILS, RECURRENT INFECTIONS

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8
Q

What is celiac neutropenia? specific failure of neutrophil maturation

A

AD, episodic neutropenia every 4-6 weeks

mutation in neutrophil elastase (ELA-2)

NO NEUTROPHILS, RECURRENT INFECTIONS

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9
Q

What condition is failure to express leukocyte adhesion markers?

A

Leukocyte adhesion deficiencies (LAD)

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10
Q

What is LAD?

A

deficiency of CD18 (b2 integral subunit)

Normal = CD11a/CD18 (LFA-1) on neutrophils bind to ICAM-1 on endothelium for adhesion and transmigration

LAD = neutrophils lack LFA-1

  • very high neutrophil count in blood
  • absence of pus formation

DELAYED UMBILICAL CORD SEPARATION AT BIRTH

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11
Q

What condition is failure of oxidative killing?

A

Chronic Granulomatous Disease (CGD)

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12
Q

What is CGD?

A

Cause = absent respiratory burst:

  • Deficiency of one of components of NADPH oxidase
  • Inability to generate O2 free radicals so impaired killing

Signs & symptoms:

  • Excessive inflammation:
    • Persistent neutrophil/macrophage accumulation
    • Failure to degrade antigens
  • Granuloma formation
  • Lymphadenopathy and hepatosplenomegaly

Tests: DHR and NBT tests (both -ve in CGD)

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13
Q

Tests for CGD

A

NBT and DHR both -ve in CGD

stays yellow

no fluorescing

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14
Q

Give condition(s) for failure of cytokine production aka which cytokines?

A

IFNg + IL-12 network failure

  • cytokine deficiency of IL-12, IL-12-r, IFNg, IFN-r

IFNg-IL12 network important in control of mycobacteria infection:

  • Infection activates IL12-IFNg network
  • Infected macrophages produce IL12
  • IL12 induces T cells to secrete IFNg
  • IFNg feeds back to macrophages & neutrophils
  • Stimulates production of TNF
  • Activates NADPH oxidase  oxidative pathways
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15
Q

2 types of NK cell deficiency

features

A

Classical NK deficiency:

  • Absence of NK cells within peripheral blood
  • Abnormalities described in GATA2 or MCM4 genes in subtypes 1 and 2

Functional NK deficiency:

  • NK cells present but function is abnormal
  • Abnormality described in FCGR3A gene in subtype 1

Features… child with severe chicken pox and disseminated CMV infection (viral!!!) HHV and HPV infection

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16
Q
  1. young child with recurrent infections, high neutrophil count on FBC but no abscess formation
  2. child with recurrent infections with hepatosplenomegaly and abnormal DHR test (does not fluoresce)
  3. baby with recurrent infections and no neutrophils on FBC
  4. young man with infection with atypical mycobacterium. Normal FBC.
  5. Child with severe chicken pox and disseminated CMV infection
A
  1. young child with recurrent infections, high neutrophil count on FBC but no abscess formation = LEUKOCYTE ADHESION DEFICIENCY
  2. child with recurrent infections with hepatosplenomegaly and abnormal DHR test (does not fluoresce) = CGD
  3. baby with recurrent infections and no neutrophils on FBC = KOSTMANN SYNDROME
  4. young man with infection with atypical mycobacterium. Normal FBC = IFNg RECEPTOR DEFICIENCY
  5. Child with severe chicken pox and disseminated CMV infection = CLASSICAL NK CELL DEFICIENCY
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17
Q

What infections can you get from complement deficiency? TERMINAL COMMON PATHWAY

A

Inability to make membrane attack complexa → Inability to use complement to lyse encapsulated bacteria

susceptibility to bacterial infections (especially encapsulated bacteria aka NHS)

  • Neisseria meningitides = esp. properdin deficiency + C5-9 deficiency
  • Haemophilus influenzae
  • Streptococcus pneumonia
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18
Q

MBL deficiency

A
  • MBL2 mutations are common but not usually associated with immunodeficiency
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19
Q

C1,2,4 deficiency (classical pathway) features

A

C1,2,4 deficiency → increased risk of SLE/autoimmunity

classical → phagocyte mediated clearance of apoptotic/necrotic cells

  • deficiencies → self-antigens uncleared → autoimmunity and immune complexes (i..e SLE)
  • self-antigens are often nuclear components

Classical → clearance of immune complexes by erythrocytes

  • deficiencies → immune complex deposition → local inflammation in skin, joints and kidneys
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20
Q

C3 nephritic factor (anti-C3-convertase) → depletes C3

associations

A

glomerulonephritis (membranoproliferative)

partial lipodystrophy

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21
Q

How do we manage complement deficiencies?

A
  • vaccination (meningovax, pneumovax, HIB)
  • prophylactic abx
  • tx infection aggressively
  • screening of family members
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22
Q

complement ix’s

A

C3 and C4 levels

functional complement tests:

  • CH50 classical pathway (CH)
  • AP50 alternative pathway (AP) = properidin, factors B and D
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23
Q

12-year-old presents with meningococcal septicaemia with family history of sibling dying of same condition aged 6. No features of SLE, no proteinuria, normal fat distribution. Which is the most likely complement deficiency?

24-year-old woman with membranoproliferative nephritis and abnormal fat distribution.

9-year-old girl with severe SLE and normal levels of C3 and C4. What is the most likely complement deficiency?

A

12-year-old presents with meningococcal septicaemia with family history of sibling dying of same condition aged 6. No features of SLE, no proteinuria, normal fat distribution. Which is the most likely complement deficiency? C7 DEFICIENCY

24-year-old woman with membranoproliferative nephritis and abnormal fat distribution. C3 DEFICIENCY WITH PRESENCE OF A NEPHRITIC FACTOR

9-year-old girl with severe SLE and normal levels of C3 and C4. What is the most likely complement deficiency? C1q DEFICIENCY

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24
Q
  1. A child has deficiency of Properidin. Which of the following tests would you expect to be abnormal?
A
  1. Alternative pathway (AP) 50
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25
complement deficiencies summary
26
Innate immune response immunodeficiencies
27
Complement pathways summary
28
Clinical features of T-cell deficiencies
**Viral** infections (CMV) **fungal** infections (pneumocystis - CD4 T cell cytokines needed to control PCP; Cryptosporidium) Some **bacterial** infections (esp. intracellular organisms → MTB, salmonella) Early malignancy
29
Ix of T cell deficiencies
30
Mx of T cell immunodeficiency
_Aggressive prophylaxis/tx of infection_ _HSCT:_ * replace abnormal populations in **SCID** * replace abnormal cells = Bare Lymphocyte Syndrome Class II **(BLSCII)** _Enzyme replacement therapy:_ * **PEG-ADA for ADA SCID** _Gene therapy:_ * stem cells treated **ex-vivo with viral vectors** containing missing components * transducer cells have survival advantage in vivo _Thymic transplantation:_ * Promote T cell differentiation in **Di George syndrome** * Cultured donor thyme tissue transplanted to quadriceps muscle
31
Give 2 examples of failure of lymphocyte precursor
SCID (X-linked SCID, ADA deficiency)
32
X-linked SCID → failure to respond to cytokines X-LINKED SO MOSTLY BOYS
**45%** of all SCID mutation of **common gamma chain** on Chromosome X (q13.1) * shared by receptor for IL2/4/7/9/15/12 → _inability to respond to cytokines_ * **early arrest of Tc and NK** development, and production of **immature Bc**
33
ADA (adenosine deaminase) deficiency → inability to respond to cytokines BOYS OR GIRLS
16.5% of all SCID enzyme that lymphocytes require for cell metbaolism * inability to respond to cytokines * early arrest of Tc and NK development * **NO Bc production**
34
Are neonates protected from SCID/ADA deficiency?
In the **first 3 months of life,** the neonate is **protected** from SCID and ADA deficiency from: * **IgG** from the _maternal placental supply_ * IgG from _breast milk colostrum_ – *however this is not as good and leads to eventual drop of IgG*
35
KEY difference between X-linked SCID and ADA deficiency
SCID = immature Bc ADA deficiency = very low/absent Bc
36
Give a condition that is failure of thymic development?
Di George Syndrome (**22q 11.2 deletion** syndrome, a developmental defect of the pharyngeal pouch)
37
Features of Di George Syndrome How do we detect DGS Phenotype and genetics
**CATCH-22:** * Cardiac abnormalities (ToF) * Abnormal facies (high forehead, low-set and folded ears, micrognathia, broad nasal bridge) * Thymic aplasia (+/- oesophageal atresia) * Cleft palate * Hypocalcaemia, hypothyroidism * 22q 11.2 Not mentally retarded but _higher schizophrenia_ as an adult Detected by **FSH cytogenetic analysis** Phenotype: * Normal Bc number * **Reduced Tc number** → only a mild impairment of immunity that **improves with age** * could present with _PCP pneumonia_ and _atypical viral infections_ (need Tc to control these) Genetics: * deletion **22q11.2 (TUPLE locus)** * **TBX1** responsible for some features
38
Give a condition that's failure of expression of HLA molecules
Bare Lymphocyte Syndrome (type 2) → absent MHC class 2
39
Bare Lymphocyte Syndrome (type 2) → absent MHC class 2 which proteins affected phenotype
Bare Lymphocyte Syndrome (type 2) → absent MHC class 2 Absent expression of MHC Class II molecules *(BLS type 1 exists when MHC class 1 fails to express)* Defect in a regulatory protein involved in Class II gene expression * **Regulatory factor X** * **Class II transactivator** Phenotype: * **T-cells** = **low CD4 cells**; normal CD8 cells * **B-cells** = normal; **BUT** low IgG or IgA antibody (due to lack of CD4+ T cell help)
40
1. Severe recurrent infections from 3 months, CD4 and CD8 T cells absent, B cell present, Ig low. Normal facial features and cardiac echocardiogram. Which is the most likely diagnosis? 1. Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, reduced numbers of T cells, low IgA and IgG. Which is the most likely diagnosis? 1. 6-month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG low.
1. Severe recurrent infections from 3 months, CD4 and CD8 T cells absent, B cell present, Ig low. Normal facial features and cardiac echocardiogram. Which is the most likely diagnosis? **X-LINKED SCID** 1. Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, reduced numbers of T cells, low IgA and IgG. Which is the most likely diagnosis? **BARE LYMPHOCYTE SYNDROME (CLASS 2)** 1. 6-month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG low. **BARE LYMPHOCYTE SYNDROME (CLASS 1)**
41
Tc deficiency summary
42
Tc deficiency summary
43
Features of Bc (or CD4 Tc) deficiency → antibody deficiency (3)
* bacterial infections (Staph, Strep) * Toxins (tetanus, diphtheria) * some viral infections (enterovirus)
44
Ix for Bc deficiencies
44
Ix for Bc deficiencies
45
Mx of Bc immunodeficiency
Aggressive prophylaxis/tx of infection **IVIG:** * derived from pooled plasma from thousands of donors * contains _IgG antibodies_ to a wide variety of common organisms * aim of maintaining trough IgG levels within the normal range * tx is life-long **Immunisation** (_ONLY IN SELECTIVE IgA DEFICIENCY)_ * not otherwise effective because of defect in IgG antibody production
46
Give a condition that is failure of Bc maturation
Bruton's X-linked hypogammaglobulinaemia
47
**Bruton’s X-linked hypogammaglobulinaemia**:
* Abnormal **B-cell tyrosine kinase** (BTK) gene * Pre-B-cells cannot develop to mature B cells → **_absence_** of mature B-cells * **No circulating Ig** after ~3 months (i.e. no IgG, IgA or IgM) * _Mx: IVIG_
48
Give a condition that is failure of Tc costimulation?
**X-linked** **(recessive) hyper-IgM syndrome** **syndrome** due to CD40 ligand mutation:
49
X-linked (recessive) hyper-IgM syndrome due to CD40 ligand mutation
Genetic mutations = mutation in **CD40 ligand** gene (CD40L, CD154) * Member of the TNF-r family * Encoded on Xq26 * Involved in **T-B-cell communication** * Ligand expressed by activated T cells (NOT on B cells) Phenotype: * B-cells = normal * T-cells = normal **(but no CD40 ligand expressed)** * No germinal centre development within lymph nodes and spleen * **_Failure_** of isotype switching * **IgM** high * **IgA**, **IgE**, **IgG** undetectable
50
What is the condition for failure or production of IgG antibodies (2)
Common variable immune deficiency Selective antibody deficiency
51
Core features of common variable immunodeficiency
Core features: * **Low IgG, IgA and/or IgE** * **Poor/absent response to immunisation** * Absence of other defined immunodeficiency * **Atypical SLE** common, recurrent bacterial infections (i.e. bronchiectasis may be present) Cause unknown Heterogenous group of disorders: * Many different genetic defects (most unidentified) * Failure of differentiation/function of B cells
52
Clinical features of common variable immunodeficiency
53
Selective features of selective IgA deficiency
* 1 in 600 prevalence * 2/3rds individuals **asymptomatic** * 1/3rd have **recurrent RTIs** * Genetic component but cause unknown
54
1. 1-year-old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent. 2. Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, high IgM, absent IgA and IgG. 3. Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE. 4. Recurrent RTIs, absent IgA, normal IgM and IgG.
1. 1-year-old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent. **BRUTON'S X-LINKED HYPOGAMMAGLOBULINAEMIA** 2. Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, high IgM, absent IgA and IgG. **X-LINKED HYPER-IGM SYNDROME DUE TO CD40 LIGAND MUTATION** 3. Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE. **COMMON VARIABLE IMMUNODEFICIENCY** 4. Recurrent RTIs, absent IgA, normal IgM and IgG. **IgA DEFICIENCY**
55
Summary of Bc Deficiencies
56
Summary of types of primary immunodeficiencies
56
Summary of types of primary immunodeficiencies
57
SUMMARY OF IT ALL
58
Innate natural barriers summary
59
Complement deficiencies tests
60
Infections from lymphocyte deficiencies Mx of lymphocyte deficiencies
60
Infections from lymphocyte deficiencies Mx of lymphocyte deficiencies

Year 5 Immunology (5 decks)

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