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Matt's Path > Immune Deficiencies > Flashcards

Immune Deficiencies Flashcards

1
Q

Reticular Dysgenesis

A

Autosomal Recessive SCID
AK2 mutation = adenylate kianse 2 in mitochondria responsible for energy production

Causes failure of stem cells to differentiate along MYELOID AND LYMPHOID linage

Failure of production of:
Neutrophils
Lymphocytes
Monocyte/macrophages 
Platelets
Fatal in very early life unless corrected with bone marrow transplantation
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2
Q

Kostmann Syndrome

A

Autosomal recessive severe congenital neutropenia

Solely affects neutrophil maturation

HAX1 mutation

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3
Q

Cyclic Neutropenia

A

Autosomal dominant episodic neutropenia
Every 4-6 weeks

Neutrophil elastase (ELA-2) mutation

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4
Q

Leukocyte Adhesion Deficiency

A

Deficiency of CD18 / B2 integrin

CD11a/CD18 on neutrophil bind to endothelium and facilitate extravasation

Causes:
Very high neutrophils in the blood
Absence of pus formation

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5
Q

Chronic Granulomatous Disease

A

Failure to generate respiratory burst

NADPH oxidase deficiency

Persistent neutrophil/macrophage accumulation

Formation of Granuloma

Lymphadenopathy and hepatosplenomegaly

Can give IFN-y to activate additional pathways in place of oxidative killing

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6
Q 
Nitroblue tetrazolium (NBT) test AND 
Dihydrorhodamine (DHR) flow cytometry test
A

Combined = can neutrophils kill through production of oxidative free radicals

Nitroblue tetrazolium NBT
NBT is a dye that changes colour from yellow –> blue, following interaction with hydrogen peroxide
(Nellow to Blue)

Dihydrorhodamine DHR
DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

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7
Q

Treatment of phagocyte deficiencies

A 
Aggressive management of infection
Infection prophylaxis
Septrin – antibiotic
Itraconazole – anti-fungal
Oral/intravenous antibiotics as needed
Surgical draining of abscesses
Definitive therapy	
Bone marrow transplantation
‘Replaces’ defective population
Specific treatment for CGD
Interferon gamma therapy
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8
Q

Immunodeficiency involving phagocytes

A

Reticular dysgenesis
Kostmann syndrome (congenital neutropenia)
Leukocyte adhesion deficiency
Chronic granulomatous disease
IL12 /IFN gamma cytokine or receptor deficiency

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9
Q

Activation of the Complement Cascade

A

Classical = antibody-mediated

Lectin = MBL to microbial cell surface carbohydrates

Alternative = Spontaneous breakdown of C3

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10
Q

Classical Pathway

A

Antibody-antigen complex (C1–>C4–>C2)

Antibody changes shape –> allows C1 to bind

C1 –> C1a

C1a –> C4 to produce C4b + C4a

C4b + C2 –> C3

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11
Q

Lectin Pathway

A

Mannose-binding lectin (MBL) C4 and C2
(independent of acquired response)

Activated by the direct binding of MBL to microbial cell surface carbohydrates

Directly stimulates the classical pathway, involving C4 and C2

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12
Q

Alternative Pathway

A

Spontaneous, C3 BIP pathway

Directly triggered by binding of C3 to bacterial cell wall components
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria

Not dependent on acquired immune response

Involves factors B, I and P

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13
Q

Features of Complement Deficiency

A 
Susceptibility to infection
Particularly with encapsulated bacteria – if alternative / terminal pathway involved
Neisseria meningitides (Meningococcus)
Streptococcus pneumoniae (Pneumococcus)
Group B streptococcus
Haemophilus influenza

FHx of meningitis

SLE
If early classical pathway missing
Classical complement pathway is involved in clearance of apoptotic/necrotic cells
Also these immune complexes will do more damage once they have developed as they won’t be solubilised and cleared – role of complement
More likely to get skin disease with SLE

ALSO
SLE causes secondary deficiency

C4 levels falls
Then C3 levels fall

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14
Q

Secondary Causes of Complement Deficiency

A

SLE
C4 levels falls
Then C3 levels fall
Due to increase consumption in solubilising immune complexes

Auto-immune condition activating C3 convertase
Nephritic Factor
auto-antibodies directed against components of the complement pathway
Associated with Glomerulonephritis (classically membranoproliferative)
Associated with partial lipodystrophy
Abdomainal fat distribution
Loss in upper half of body

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15
Q

Investigation of the Complement Pathway

A

Measure complement levels
C3 and C4 routine
C1 inhibitor: decreased in hereditary angioedema

Functional complement tests
CH50 classical pathway
AP50 alternative pathway

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16
Q

Immunodeficiency involving complement

A 
Classical pathway deficiencies
MBL deficiency 					
Alternative pathway deficiencies
C3 deficiency
Terminal pathway deficiencies
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17
Q

Phenotype of SCID

A 
SCID --> Graft vs Host Disease
Unwell by 3 months
Infections of all types
Failure to thrive
Unusual skin disease 
Maternal lymphocyte colonise infants bone marrow --> Graft vs Host 
FHx of early infant death

Protected for first 3 months:
Maternal IgG crosses placenta
Maternal antibodies protect neonate for first 3 months of life
IgG in colostrum - Neonate gut can still absorb antibodies

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18
Q

X-Linked SCID

A

X-linked SCID = 45% of all SCID

Chromosome X: IL-2R gamma chain mutation (Xq13.1)

Receptor chain is shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 RECEPTORS

Inability to respond to cytokines –> arrested T cell and NK development –> don’t produce
Able to produce immature B cells

Phenotype
Low/Absent T cells
Normal/High B cells (immature)
Poorly differentiated lymphoid tissue and thymus

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19
Q

DiGeorge

A

Chromosome 22q11.2 deletion syndrome

Forehead –> heart defects

Defect in development of the pharyngeal pouch
Thymus under developed
Majority of cases mild defect with generation later on

Phenotype
High forehead
Low set, abnormally folded ears 
cleft palate, small mouth and jaw
Hypocalcaemia
Oesophageal atresia
T cell lymphopenia
Complex congenital heart disease
Normal numbers B cells
Reduced numbers T cells  
Homeostatic proliferation with age
Immune function usually only mildly 
impaired and improves with age
20
Q

Bare Lymphocyte Syndrome Type II

A

Type II = MHC II deficiency

MHC II deficiency –> lack of selection of CD4 cells –> deficiency in CD4 cells

Mutation in MHC II regulatory proteins (NOT MHC II gene themselves)
Regulatory Factor X
Class II transactivator

Absent MHC II expression –> Lack of CD4 cells
Normal CD8 cells
Normal number of B cells
But deficiency of IgG and IgA as need CD4 to class switch

Phenotype
Unwell by 3 months
Failure to thrive 
Infections of all type
FHx of early infant death

Associated with Sclerosing Cholangitis

21
Q

IL-12 - IFN-y Deficiency

A 
Causes
IL-12 def
IL-12 R def
INF-y def
INF-yR def

Infected macrophage –> produces IL-12 –> acts on T cells, produce IFN-y –> acts back on macrophages –> Increase in TNF and NADPH oxidase activity

Susceptibility to:
Tuberculosis
Atypical mycobacteria 
BCG infection after immunisation
Salmonella

Inability to form granulomas

22
Q

Immunodeficiency Involving T cells

A

Severe combined immunodeficiency (SCID)

22q11.2 deletion syndromes

Bare lymphocyte syndrome

IL12 receptor deficiency

IFN gamma deficiency

23
Q

Management of T cell Deficiencies

A

Infection prophylaxis

Aggressive treatment of infection

Immunoglobulin replacement
If there is associated deficient antibody production

Bone marrow transplantation
To replace abnormal populations in SCID
To replace abnormal cells - class II deficient APCs in BLS

Gene therapy
Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo.
Experimental

Thymic transplantation
To promote T cell differentiation in Di George syndrome
Cultured donor thymic tissue transplanted to quadriceps muscle
- Experimental

24
Q

Bruton’s X-Linked Hypogammaglobulinaemia

A

Abnormal B cell tyrosine kinase gene = diagnostic

Pre-B-Cells cannot differentiate into mature B cells

Deficiency of mature B cells
No circulating antibodies after 3 months

Recurrent infections during childhood
Bacterial
Enterovirus

25
Q

Hyper IgM Syndrome

A 
X-linked genetic defect in the CD40L
Chromosome Xq26 (TNF receptor family)

Defect in CD4 cells that manifests as B cell defect

CD40L is expressed by ACTIVATED CD4 cells –> activates B cells and induces class switching

Deficiency of CD40L
Intrinsic T cell defects
Hyper IgM B cells: can differentiate into plasma cells BUT no class-switching (no germinal centre reaction)

Normal number of T cells
Normal number of B cells
No IgA, No IgG 
Elevated IgM in serum
No germinal centre development in the lymph nodes/spleen
Failure of isotype switching
Presentation
Boys present in first few years
Failure to thrive
Autoimmune disease
Malignancy
Pneumocystis jiroveci (PCP) infection

Intrinsic T cell defect –>Defective T cell regulation and apoptosis

  • -> T cell-impaired immunity (PCP)
  • -> Autoimmunity
  • -> Malignancy
26
Q

Selective IgA Deficiciency

A

IgA deficiency

1 in 600
2/3 asymptomatic and don’t notice
1/3 recurrent respiratory tract infections
Genetic component, but cause as yet unknown

27
Q

Common Variable Immune Deficiency

A

Low IgG, IgA and IgE
Recurrent bacterial infections
Cause unknown
Failure in differentiation of plasma cells

Defined by
Marked reduction in IgG, with low IgA or IgM
Poor/absent response to immunisation
Absence of other defined immunodeficiency

Reccurent infections
Particular sinusitis and chest infection
And non-infectious inflammatory diseases

Clinical features – adults and children

Recurrent bacterial infections
Often with severe end-organ damage
Sinusitis, pneumonia, gastroenteritis

Pulmonary disease
Obstructive airways disease
Interstitial lung disease
Granulomatous interstitial lung disease (also LN, spleen)

Gastrointestinal disease
Inflammatory bowel like disease
Sprue like illness
Bacterial overgrowth

Autoimmune disease
Autoimmune haemolytic anaemia or thrombocytopenia
Rheumatoid arthritis
Pernicious anaemia
Thyroiditis
Vitiligo

Malignancy
Non-Hodgkin lymphoma

28
Q

Management of B cell deficiencies

A

Aggressive treatment of infection
Immunoglobulin replacement
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
Treatment is life-long

Bone marrow transplantation
To ‘replace’ abnormal populations – SCID, X-linked hyperIgM

Immunisation
For selective IgA deficiency
Not otherwise effective because of defect in IgG antibody production

29
Q

B Cell Deficiencies

A 
Severe combined immunodeficiency (SCID)
X-linked Bruton’s hypogammaglobulinaemia
X-linked hyperIgM syndrome 
Common variable immunodeficiency
IgA deficiency
30
Q

T cell Deficiencies

A

Bare Lymphocyte Syndrome

DiGeorge’s Syndrome

31
Q

X-linked tyrosine kinase deficiency

A

Bruton’s Agammagloulinaemia

32
Q

X-linked Xq26 CD40L defect

A

Hyper-IgM Syndrome

33
Q

HAX-1 autosomal recessive defect

A

Kostmann Syndrome

34
Q

B2/CD18 defect

A

Leukocyte adhesion deficiency

35
Q

NADPH oxidase deficiency

A

Chronic Granulomatous Disease

36
Q

ELA-1 gene defect

A

Cyclic neutropenia

37
Q

AK2 defect

A

Reticular dysgenesis

Mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2)
Prevents differentiation

38
Q

T cell deficiency presentation

A

Viral infections
Cytomegalovirus

Fungal infection
Pneumocystis, Cryptosporidium

Some bacterial infections – esp intracellular organisms
Mycobacteria tuberculosis, Salmonella

Early malignancy

39
Q

Antibody deficiency presentation

A

Bacterial infections
Staphylococcus, Streptococcus

Toxins
Tetanus, Diptheria

Some viral infections
Enterovirus

40
Q

Colonisation of infant’s empty bone marrow by maternal lymphocytes

A

SCID

Population by maternal lymphocytes = This leads to a graft vs host reaction from maternal lymphocytes

41
Q

Mutation of gamma chain of IL2 receptor on chromosome Xq13.1

A

X-linked SCID

Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells

42
Q

NBT test

A

yellow to blue

Following interaction with hydrogen peroxide

43
Q

DHR test

A

DHR is oxidised to rhodamine which is strongly fluorescent

Following interaction with hydrogen peroxide

44
Q

SLE associated complement deficiency

A

C1q, C1r, C1s, C2, C4 deficiency are all described

All are rare

C2 deficiency most common

45
Q

Nephritic factors

A

Nephritic factors are auto-antibodies directed against components of the complement pathway

Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption

Often associated with glomerulonephritis (classically membranoproliferative)

Associated with partial lipodystrophy
Abdomainal fat distribution
Loss in upper half of body

46
Q

C1 inhibitor deficiency

A

Hereditary angiooedema

Matt's Path (18 decks)

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