Primary immunodeficiencies Flashcards by a b

primary vs secondary immunodeficiencies

Primary immunodeficiencies

rare (1 in 10,000)
occurs when mutated gene -> altered protein involved in immune response

Secondary immunodeficiencies

common
subtle clinically
often involve more than 1 component of immune system

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4 examples of secondary immunodeficiences

1) Infection (HIV, measles, mycobacteria)
2) Biochemical (Zn/Fe deficiency, renal impairment, malnutrition)
3) Drugs (corticosteroids, anti-proliferative immunosuppressants and cytotoxic drugs used in Ca therapy)
4) Malignancy (myeloma, leukaemia, lymphoma)

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Physiological immunodeficiency

1) neonates (rely on maternal IgG in first few months of life)
2) pregnancy
3) elderly (immune senescence)

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Criteria for immune deficiency

2 major infections or
1 major and recurrent minor infections
in 1 year

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other features of immune deficiency

unusual sites/organisms
chronic infections
unresponsive to Tx
early tissue damage

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Clinical features of primary immune deficiencies

FHx (as primary is INHERITED)
young age at presentation
failure to thrive

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Split primary immune deficiencies into…

1) cells of innate system (phagocyte and NK cell deficiencies)
2) complement
3) cells of adaptive immune system

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Autosomal recessive severe SCID
mutation in mitochondrial energy metabolism enzyme AK2
failure myeloid and lymphoid stem cells to differentiate
No neutrophil/lymphocyte/monocyte/macrophage/platelet production

Reticular dysgenesis

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recurrent infections in child with no neutrophils on FBC

Kostmann syndrome

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congenital neutropenia
autosomal recessive
specific failure of neutrophil maturation
mutation in HCLS1- associated HAX-1 in classical form

Kostmann syndrome

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Recurrent episodic infections with episodic neutropenia on FBC

Cyclic neutropenia

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failure of neutrophil maturation
autosomal dominant
episodic neutropenia every 4-6wks
mutation in neutrophil elastase (ELA-2)

Cyclic neutropenia

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Recurrent infections in child with high neutrophil count on FBC but no abscess formation

Leukocyte adhesion deficiency

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Failure of neutrophils or leukocytes to migrate to site of infection
production still normal
deficiency of CD18 (b2 integrin subunit) adhesion molecule on neutrophil
Neutrophils cannot migrate from blood -> tissue

Leukocyte adhesion deficiency

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High neutrophil count in FBC
Absence of pus formation/abscess
delayed umbilical cord separation in neonate

Leukocyte adhesion deficiency

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Recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test (does not fluoresce)

Chronic granulomatous disease

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deficiency in component of NADPH oxidase
cannot generate O2 free radicals (hydrogen peroxide)
DHR and NBT test negative

Chronic granulomatous disease

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excessive inflammation 
granulomas 
lymphadenopathy
hepatosplenomegaly
susceptibility to catalase +ve bacteria (Pseudomonas, Listeria, Aspergillus, Candida, E.coli, S. Aureus, Serratia)

Chronic granulomatous disease

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Infection with atypical mycobacterium. Normal FBC

IFN gamma receptor deficiency

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deficiency of IFN-g and IL-12 and their receptors
susceptibility to mycobacterium infection (MTB or atypical), BCG, salmonella
Inability to form granulomas

deficiency of IFN-g and IL-12 and their receptors

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severe chicken pox, disseminated CMV infection

Classical natural killer cell deficiency

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Absence NK cells in peripheral blood

GATA2 and MCM4 subtype 1 and 2 abnormality

Classical natural killer cell deficiency

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NK cells present in blood but function abnormal

FCGR3A subtype 1 gene abnormality

Functional NK cell deficiency

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Recurrent S. Aureus or enteric or Candida or Aspergillus infections of skin or mouth
or mycobacterium infection
in a young person

phagocyte deficiency

reticular dysgenesis
Kostmann syndrome
cyclic neutropenia
leukocyte adhesion deficiency
IL-12/IFN-g and receptor deficiency

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Diagnosis of phagocyte deficiencies

``` NBT test (stays yellow) DHR test (no fluorescence) ``` .... as no hydrogen peroxide produced as no oxidative killing

Treatment phagocyte deficiencies

``` Prophylactic antimicrobials (Septrin) Prophylactic antifungals (Itraconazole) Bone marrow transplant is definitive treatment ```

Treatment for Chronic Granulomatous disease

IFN gamma (cytokine therapy)

Neutrophil - low Leukocyte Adhesion Markers - normal NBT - usually low Pus - no

Kostmann syndrome (congenital neutropenia)

Neutrophil - high Leukocyte Adhesion Markers - low NBT - normal Pus - no

Leukocyte adhesion deficiency

Neutrophil - normal Leukocyte Adhesion Markers - normal NBT - low Pus - yes

Chronic granulomatous disease

Neutrophil - normal Leukocyte Adhesion Markers - normal NBT - normal Pus - yes

IL-12/IFN-g or receptor deficiency

>20 proteins produced by liver present in blood, inactive when activated, engage in rapid biological cascade

Complement

3 pathways in complement activation

Classical (C1,C2,C4) MBL Alternative pathway .... all converge to activate C3, then final common pathway (C5-9), then activate membrane attack complex

``` Which Complement pathway is: Activated by Ab-Ag immune complexes C1 binds to complex Activated late as dependent on antibodies dependant on acquired immune response ```

Classical pathway (C1/2/4)

Which Complement pathway is: Activated by direct binding MBL to microbial cell surface carbohydrates Stimulates C4 and C2

Mannose binding lectin pathway

Which Complement pathway is: Constantly at low level of activation that is negatively regulated Bacterial cell walls increase activation of pathway involves factors B, D and Properidin Controlled by Factor H protein

Alternate pathway

Convergence of 3 complement pathways

... onto C3 (major amplification step) triggers formation of membrane attack complex via C5-9) MAC forms holes in bacterial cell membrane -> cell death

Roles of complement fragments released during complement cascade

- increase vascular permeability and cells to site of inflammation - promote clearance of immune complexes - opsonisation to promote phagocytosis - activates phagocytes - promotes mast cell/basophil degranulation - punches holes in bacterial membranes

Alternate pathway deficiency (rare) prone to recurrent encapsulate bacterial infections

Factor B/ I / P deficiency

prone to infections and SLE (skin and joint disease)

classical pathway complement deficiency C2 deficiency commonest in SLE Also C1q, C1r, C1s, C4 in SLE

How does deficiency in complements of classical pathway lead to SLE?

1) less promotion of phagocyte-mediated clearance of apoptotic cells/immune complexes 2) increased load of self-antigens and antibodies to seld-antigens

Active lupus causes depletion of complement (usually C4, also C3)

acquired SLE | leads to persistent production immune complexes and -> depletion of complement

recurrent infections when neutropenic after receiving chemotherapy but previously well

MBL deficiency

not usually associated with immunodeficiency | increased infection rates in chemotherapy patients, HIV, antibody deficiency, premature infants

MBL deficiency

Severe childhood onset SLE with normal levels of C3 and C4

C1q deficiency (inherited)

Encapsulated bacteria (NHS)

Neisseria meningitidis (meningococcus) Haemophilus Influenzae Streptococcus Pneumonia

High risk infection from encapsulated bacteria (NHS) | high risk of connective tissue disease

C3 deficiency (primary_)

Membranoproliferative nephritis and bacterial infections

C3 deficiency with presence of a nephritic factor

Glomerulonephritis and partial lipodystrophy | and bacterial infections

C3 deficiency (secondary/acquired)

Meningococcus meningitis with FH of sibling dying of same condition aged 6

C7 or C9 deficiency

high risk of severe encapsulated bacterial infections | FH of death due to severe infection

terminal common pathway deficiency | -> inability to make membrane attack complex -> cannot use complement to lyse encapsulated bacteria (NHS)

test for classical pathway complement

CH50 | tests C1,2,4, C3, C5-9

test for alternate pathway complement

AP50 | tests for factors B,D, properidin, C3, C5-9

C3 + C4 + CH50 low AP50 +

``` C1q deficiency (deficiency in classical pathway, associated with SLE) ```

C3 + C4 + CH50 + AP50 low

Factor B deficiency | alternate pathway deficiency

C3 + C4 + CH50 low AP50 low

C7 or C9 deficiency | AP50 and CH50 both low, hence deficiency in terminal common pathway C5-9

C3 + or low C4 low CH50 + or low AP50 +

SLE C3/CH50 may be low as SLE depletes complement levels

Treatment of complement deficiencies

1) Vaccinations (HIB, Pneumovax, Meningovax) 2) Prophylactic Antibiotics 3) High level suspicion and early Tx 4) Screen family members (and Tx with 1 and 2)

Cell components of adaptive immune system

``` T cells (CD4 and CD8 Tc) B cells (Bc, plasma cells, antibodies) Soluble components (cytokines and chemokines) ```

T cell Immunodeficiencies 1) Disorder of Bone marrow 2) Disorder of thymus (x2) 3) Disorder in periphery

1) SCID (X-linked) 2) Di George syndrome (22q11 deletion syndrome), and Bare lymphocyte syndrome Type 1+2 3) IL-12/IFN-g and their receptors deficiency

Clinical features of SCID

Unwell by 3m (maternal IgG lost at this point) Infections of all types Failure to thrive FH of early infant death Persistent diarrhoea - unusual skin disease - colonisation of infant's empty bone marrow with maternal lymphocytes - graft vs host disease (often eczematous presentation)

No pathways for SCID to develop | Causes of SCID

``` >20 possible pathways Causes: - deficiency of cytokine receptors - deficiency of signalling molecules - metabolic defects can affect Bc, Tc or NK cells dependent on exact mutation ```

3 Types of SCID

``` X-linked SCID (45% of all SCID) ADA deficiency (16.5%) Reticular dysgenesis (severe form, stem cells cannot differentiate) ```

mutation of common gamma chain of IL-2 receptor on chromosome Xq13.1 (shared by receptor for IL-2,4,7,9,15,21) Inability to respond to cytokines -> early arrest of Tc and NK cell development, and immature Bc Low NK cells, low Tc normal/high Bc low Igs

X-linked SCID | NB immunoglobulins low as B cells are immature

low Tc low Bc low NK cells Adenosine deaminase deficiency (enzyme required by lymphocytes for cell metabolism) inability to respond to cytokines and causes early arrest Tc and NK cells, and production of immature Bc

ADA deficiency SCID

Developmental defect of PHARYNGEAL POUCH Normal Bc, low Tc Low immune function in early years (why?) Deletion of 22q11.2 TBX1 may be responsible for some features Usually sporadic

DiGeorge Syndrome homeostatic proliferation increases with age -> immune function improves with age

CATCH-22O

(clinical features of DiGeorge) Cardiac abnormalities (tetralogy of Fallot) Abnormal face (high forehead, small jaw/mouth, low set ears) Thymus aplasia (-> low Tc) Cleft palate Hypocalcaemia/hypoparathyroidism 22q11.2 delection syndrome Oesophageal atresia

Defect in regulatory protein involved in Class I or II gene expression (what are proteins called?)

proteins involved = regulatory factor X and Class II transactivator Bare lymphocyte Syndrome - Type 1 = low HLA class I -> low CD8 Tc - Type II = low HLA class II -> low CD4 Tc

very low CD4 Tc normal CD8 Tc normal Bc low IgF or IgA

Bare lymphocyte syndrome type II

normal CD4 Tc low CD8 Tc normal Bc

Bare lymphocyte Syndrome Type I

Clinical features of Bare lymphocyte syndrome

Unwell by 3m Infections of all types may be associated with SCLEROSING CHOLANGITIS FH of early infant death

abnormality in cytokine release by Tc | risk of mycobacterium infections, BCG and salmonella

Deficiency of IL-12, IFN-g and their receptors

Failure to express CD40L on activated Tc | leads to abnormal T-Bc communication

Hyper IgM syndrome

``` Severe recurrent infections from 3m CD4 and CD8 Tc absent Bc present Igs low Normal facial features and cardiac ech ```

X-linked SCID

Young adult with Mycobacterium marinum infection

IFN gamma receptor deficiency

``` Recurrent infections in childhood abnromal facial features congenital heart disease normal Bc low Tc low IgA and G ```

DiGeorge Syndrome

6m old baby with 2 recent bacterial infections Only CD8 Tc present Bc present IgM present, IgG low

Bare lymphocyte syndrome Type 2

Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE

Common variable immunodeficiency

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

1 year old boy recurrent bacterial infections. CD4 and CD8 Tc present Bcells absent, IgG/A/M absent

Brutons X linked hypogammaglobulinaemia

Recurrent respiratory tract infections, absent IgA , normal IgM/G

IgA deficiency

Increased risk mycobacterium infections, BCG, Salmonella Cannot form granulomas T cells cannot interact with macrophages

IL-12, IFN-g and receptors deficiency

Failure to express CD40L on activated T cells Hence no T-B cell interaction IgM B cells cannot undergo germinal centre reaction

Hyper IgM Syndrome

Normal Bc Normal Tc High IgM low IgA, IgG, IgE

Hyper IgM Syndrome

Boys present with failure to thrive in first few years of life with Recurrent bacterial infections Higher risk Pneumocystis jiroveci infections, autoimmune disease and malignancy

Hyper IgM Syndrome

Defective B cells tyrosine kinase gene Pre B cells cannot develop into mature B cells No mature B cells No circulating Ig after 3m

Bruton's X-linked hypogammaglobulinaemia

Defective B cell tyrosine kinase gene Boys present in 1st few years of life, failure to thrive, recurrent bacterial infections: Otitis media, sinusitis, pneumnia, osteomyelitis, septic arthritis, gastroenteritis Viral, fungal, parasitic infections (enterovirus, pneumocystis)

Bruton's X-linked hypogammaglobulinaemia

2/3 asymptomatic 1/3 recurrent respiratory tract infections and GI infections Incidence 1 in 600 Genetic component but cause unknown

Selective IgA deficiency

failure in differentiation/function of B cells Heterogeneous group of disorders, cause unknown Low IgG, A, E Poor response to immunisation

Common variable immune deficiency

recurrent bacterial infections with severe end-organ damage (bronchiectasis, persistent sinusitis, recurrent GIT infections) Higher risk AI disease (AIHA, thrombocytopenia, RA< pernicious anaemia, thyroiditis, vitiligo) Higher risk granulomatous disease, malignancy (Non-Hodgkin's Lymphoma), pulmonary disease (interstitial lung disease)

Common variable immune deficiency

``` Defined by: - markedly low IgG, low IgA or IgM - poor/absent response to immunisation - absence of other defined immunodeficiency ```

Common variable immune deficiency

Clinical phenotype of Antibody deficiency (or CD4 T cell deficiency)

Bacterial infections (Staph, Strep) Toxins (Diptheria, Tetanus) Some viral infections (Enterovirus)

Diagnosis of B cell immunodeficiency

- White cell count - lymphocyte subsets (quantify B cells, CD4/8 T cells, NK cells) - serum Ig and protein electrophoresis - functional test of B cell function (measure IgG antibodies against tetanus, HIB etc to see if specific levels low, then immunise against those

Result of protein electrophoresis where no Antibodies being produced

no peak in gamma wave

Mx of B cell deficiencies

- Aggressive treatment of infection - Lifelong Ig replacement (every 3 weeks) of pooled plasma containing diverse IgG against lots of different organisms - bone marrow transplant - immunisation in IgA deficiency (not effective if no IgG)

Primary immunodeficiencies Flashcards

(95 cards)