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PATH FINAL > Primary Immune Deficiencies 2 > Flashcards

Primary Immune Deficiencies 2 Flashcards

1
Q

Largest Innate Immunity cell in blood

A

Neutrophil

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2
Q

Neutrophil production in the __________ __________ is regulated by __________

A

Neutrophil production in the bone marrow is regulated by IL-17-G-CSF axis

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3
Q

Main actions of Neutrophils

A

Phagocytosis
Degranulation
NETosis (formation of neutrophil extracellular traps)

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4
Q

2 main types of inborn errors of immunity affecting neutrophils

A

Quantitative neutrophil defects (low levels)

Defects in neutrophil function
* binding to endothelial cells (migration) = Leukocyte adhesion deficiency syndromes (rare!)
* Generation of reactive oxygen species = Chronic Granulomatous Disease (CGD)

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5
Q

Outline the different classifications of neutropenia severities

A

1.0-1.5 x109/L —> Mild
0.5-1.0 x109/L —> Moderate
0.2-0.5 x109/L —> Severe
<0.2 x109/L —> Very severe

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6
Q

What are the 2 main quantitative neutrophil deficiency syndromes

A

Chronic benign neutropenia
- Mild (usually) or moderate neutropaenia
- Common in number of different ancestry groups
- Asymptomatic (should not lead to further investigations!)

Severe congenital Neutropenia
- defects in neutrophil maturation + commonly a mutation on neutrophil elastase
- Present within 3 months of life
- Susceptible to oral, cutaneous Staph (a, epi), G-enteric bacteria and fungal infections
- Life threateneing infections develop if not recognised and treated promprly
- May exist alongside other haematological malignancies as genetic defects may predispose to these malignancies (e.g. AML)
- Treatment: G-CSF support and Stem cell transplantation for high risk individuals

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7
Q

Pathophysiology of Leukocyte Adhesion Deficiency

A

A type of inborn error of immunity relating to neutrophil migration

Deficiency of CD18 (beta 2 integrin subunit) - CD18 is expressed on neutrophils which binds to ligand ICAM-1 on endothelial cells regulating neutrophil adhesion/transmigratiom. Lack of CD18 results in neutrophils failing to exit from bloodstream.

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8
Q

Clinical picture of Leukocyte Adhesion Deficiency

A
  • Delayed seperation of umbilical cord
  • Severe Neutrophilia (20-100 x106/L)
  • Abscence of pus formation
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9
Q

Outline the pathophysiology of chronic granulomatous disease

A

A type of inborn error of immunity relating to neutrophil generation of reactive oxygen species

Deficiency of one of components of NADPH oxidase - preventing the formation of important oxygen free radicals resulting in impaired killing of pathogens and NETosis. (defined as absent respiratory burst)

Furthermore, due to absent reactive oxygen species there is excessive inflammation resulting in macrophage infiltration and granuloma formation causing GI and GU disease.

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10
Q

Clinical picture of CGD

A
  • Recurrent severe bacterial or fungal infections in: Skin, lymph node, liver, bone, chest
  • Increased risk of developing TB
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11
Q

Management of CGD

A
  1. Cotrimoxazole and Itraconazole prophylaxis
  2. Adjunctive IFN-gamma, stem cell and gene therapy
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12
Q

Investigations for Neutrophil IEI Syndrome

A
  • Immunoglobulins
  • Bone marrow biopsy
  • Neutrophil function assay (uses control neutrophils unstimulated, then a control stimulated to measure oxidative burst. Then compares to patients unstimulated and stimulated oxidative burst - in an IEI of neutrophil function it would result in no change between unstimulated and stimulated )
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13
Q

Outline the Complement immune reaction

A

Main opsonin is C3. There are 3 different ways in which C3 can be activated (cleaved into C3a, C3b, C3d)
- Classical activation is through Antigen-IgG complex, which activates C1 then C2 and C4 and ultimately C3
- Mannose Binding Lectin is through MBL binding to microbial cell surface carbohydrate activates C2 and C4 which ultimately activates C3.
- Alternative pathway is where C3 itself binds to bacterial cell wall PAMPs

Once activated C3 is cleaved into:
- C3a –> induces acute inflammatory response
- C3b –> opsonisation of pathogens
- C3d –> modulate adaptive immune response by lowering B and T cell receptor signalling threhsold prepping them for activation

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14
Q

Main functions of complement immune reaction

A
  • Induces acute inflammatory response (C3a)
  • Oponisation of pathogens (C3b)
  • Regulation of B and T cell immune responses (C3d)
  • Removal of immune complexes
  • Control of Neisseria infection
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15
Q

List the different Complement protein deficiencies

A
  • C1, C2, C4 Deficiency (classical pathway deficiency)
  • MBL deficiency
  • C3 deficiency
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16
Q

Outline the clinical picture of C1,2,4 deficiency

A
  • Increased risk of SLE
  • Susceptibility to encapsulated bacterial infections ( H. influenzae b, Step. pneumoniae)
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17
Q

Outline the clinical picture of MBL deficiency

A

Common but not usually associated with immunodeficiency

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18
Q

Outline the clinical picture of C3 deficiency

A

Pyogenic bacterial infection
C3 glomerulonephritis

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19
Q

Investigations for complement immunity deficiency

A
  • Levels of C3 and C4
  • Functional complement tests (CH50 for classical and AP50 for alternative pathway)
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20
Q

What are the 3 main bacteria you are more susceptible to in complement deficiencies

A

Encapsulated bacteira - especially (NHS):
Neisseria meningitides
Haemophilius Influenzae
Streptococcus Pneumoniae

21
Q

Management of patients with complement protein deficiencies

A
  1. Vaccination (boost protection mediated by other arms of immune system) - Meningococcal, Pneumovax and HIB vaccines
  2. Prophylactic antibiotics
  3. Treat infections aggressively
  4. Screen family membranes
22
Q

Define “Primary Lymphoid Organs”

A

= organs involved in lymphocyte development

23
Q

Distinguish between the 2 primary lymphoid organs

A

Bone Marrow
- T and B cell derivation
- B cell maturation

Thymus
- T cell maturation (lineage commitment and function - positive selection of self-.MHC peptide)
- T cell tolerance regulation
- Most active in neonatal and foetal period

24
Q

Outline the different T-cell immune deficiencies

A
25
Q

Define SCID

A

Absence or dysfunction of T cells affecting both cellular and humoral immunity

Commonly X-linked (hence more common in boys) but can be autosomal recessive.

26
Q

What molecular impairments can lead to SCID

A
  • Metabolic diseases inhibiting lymphocyte development
  • Absent or impaired cytokine signal transduction pathways
  • Failure to form functional T cell receptor complex
  • Abnormalities in stromal component of thymus
27
Q

Differentiate between the 2 main types of SCID

A

X-linked SCID
- Mutation of common gamma chain on chromosome X = Inability to respond to cytokines
- Causes early arrest of T cell develoment and NK development

Adenosine Deaminsae Deficiency (ADA)
- deficiency of ADA (enzyme lymphocytes require for cell metabolism) = Inability to respond to cytokines
- Causes early arrest of T cell, NK development and NO production of B cells (hence in blood tests ADA SCID has low B cell numnbers while X-linked SCID has normal levels of B cells)

28
Q

Clinical picture of SCID

A
  • Onset of disease before age of 1 (often by 3 months of age)
  • Persistent viral chest and GI infections (para-influenza, adenovirus)
  • Opportunistic infections (pneumocystic jirovecii, CMV)
  • Infections from live vaccines
  • Persistent or severe mucosal and/or skin candida infection
  • Failure to thrive
  • FHx of early infant death
29
Q

Outline how SCID is diagnosis

A
  • Low lymphocyte count
  • CD3 T cell <300cells/uL
  • T cell proliferation <10% of control
  • Low serum immunoglobulins
30
Q

Treatment of SCID

A

Stem cell transplantation (HLA matched donor (can be sibling or unrelated))

If no donors = gene therapy

31
Q

Outline treatment outcomes which improve prognosis in SCID patients

A

Age less than 3.5 months - early diagnosis improves outcomes
No infection developed
Matched sibling donor

32
Q

Outline a possible screening method of SCID

A

Serum measurement of T-cell receptor excision (TREC)

TREC is a byproduct of generation of T cell receptor - hence low counts in neonates would show high chance of SCID

33
Q

What immune deficiency results in defects in T cell maturation/selection in the thymus

A

22q11.2 deletion = DiGeorge’s syndrome
(commonest chromosomal deletion syndrome)

34
Q

Clinical picture of Di George Syndrome

A

CATCH 22
- Cardiac abnormalities (teratology of fallot)
- Abnormal facies (high forehead, low-set folded ears, broad nasal bridge)
- Thymic aplasia (resulting in defects in T cell maturation/selection in thymus)
- Cleft palate
- Hypocalcaemia, hypoparathyroidisim
- 22q 11.2

35
Q

Outline the immune deficiency phenotype seen in patients with Di George Syndrome

A
  • Reduced T cell number (resolves during childhood) but can result in atypical viral infections or PCP pneumonia
  • Increased incidence of autoimmune disease (ITP) and humoral defects with age
36
Q

Outline the different B-cell immune deficiencies

A
37
Q

Commonest primary antibody deficiency syndrome

A

Selective IgA deficiency

38
Q

g

Clinical features of Selective IgA deficiency

A

Allergic disorders
Sino-pulmonary and enteric infections
Autoimmune disease (Coeliac, ITP, SLE, T1DM, autoimmune thyroid disease)

39
Q

Define Common variable immune deficiency (CVID)

A

Antibody deficiency syndrome characterised by
- Increased susceptibility to infection from encapsulated bacteria (e.g. Strep. pneum; HIB)
- Autoimmune disease
- Granulomatous disease
- Lymphoproliferative disease

40
Q

Pathogenesis of CVID

A
  • Defect in B cell function characterised by failure to make protective antibodies to polysaccharide encapsulated pathogens
  • Aetiology is largely unkonw but monogenic genetic mutation foud in 10% of pts
41
Q

Infection phenotype in patients with CVID

A

Recurrent bacterial sino-pulmonary infection from encapsulated bacteria
Repeated chest and sinus infection may result in bronchiectasis and chronic sinusitis
Enteric infection with campylobacter jejuni and Giardia lamblia

42
Q

Epidemiology of CVID

A

Commonest cause of primary antibody deficiency
1 in 20,000-50,000
Bimodal age for onset of symptoms

43
Q

Outline the phenotype in patients with Complex CVID

A

Complex CVID = autoimmune/autoinflammatory disorder alongside exisitng CVID

  • Autoimmune disorder: ITP, AIHA, Thyroid disease
  • Granulomatous interstitial lung disease - with granulomatous infiltration in lymph nodes, spleen, skin, liver
  • increased risk of B cell Non-Hodgkins Lymphoma and Gastric cancer
44
Q

Diagnosis of CVID

A
  • Reduced IgG and IgA and/or IgM more than 2 SD below reference interval for healthy control
  • Poor vaccine responses to either carbohydrate (pnuemovax) and/or protein antigen (tetanus) vaccines
  • Exclusion of other causes of antibody deficiency
45
Q

Management of CVID

A
  • Standard management for complication of lung disease (physio, saline nebuliser, standard abx)
  • IgG replacement therapy
46
Q

Define Bruton’s X-linked hypogammaglobulinaemia

A

Mutation in B-cell tyrosine kinase (BTK) gene resulting in Pre-B-Cells failing to mature into mature-B-cells

Ultimately resulting in absence of mature B cells.

47
Q

Clinical phenotype of Bruton’s X-linked hypogammaglobulinaemia

A

Recurrent bacterial pyogenic infection involving ear, nose, throat, respiratory and GI tract

Common bacteira: S. pneumoniae, H. influenzae, S. aureus, Pseudomonas spp

48
Q

Tell-tale biochemical find of Bruton’s X-linked hypogammaglobulinaemia (or any X-linked agammaglobulinaemia)

A

all types of Ig are ABSENT
Marked reduction or absent B cells

in history look for male relative on maternal side

PATH FINAL (36 decks)

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