Primary immunodeficiencies Flashcards
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
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)
Physiological immunodeficiency
1) neonates (rely on maternal IgG in first few months of life)
2) pregnancy
3) elderly (immune senescence)
Criteria for immune deficiency
- 2 major infections or
- 1 major and recurrent minor infections
- in 1 year
other features of immune deficiency
unusual sites/organisms
chronic infections
unresponsive to Tx
early tissue damage
Clinical features of primary immune deficiencies
FHx (as primary is INHERITED)
young age at presentation
failure to thrive
Split primary immune deficiencies into…
1) cells of innate system (phagocyte and NK cell deficiencies)
2) complement
3) cells of adaptive immune system
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
recurrent infections in child with no neutrophils on FBC
Kostmann syndrome
congenital neutropenia
autosomal recessive
specific failure of neutrophil maturation
mutation in HCLS1- associated HAX-1 in classical form
Kostmann syndrome
Recurrent episodic infections with episodic neutropenia on FBC
Cyclic neutropenia
failure of neutrophil maturation
autosomal dominant
episodic neutropenia every 4-6wks
mutation in neutrophil elastase (ELA-2)
Cyclic neutropenia
Recurrent infections in child with high neutrophil count on FBC but no abscess formation
Leukocyte adhesion deficiency
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
High neutrophil count in FBC
Absence of pus formation/abscess
delayed umbilical cord separation in neonate
Leukocyte adhesion deficiency
Recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test (does not fluoresce)
Chronic granulomatous disease
deficiency in component of NADPH oxidase
cannot generate O2 free radicals (hydrogen peroxide)
DHR and NBT test negative
Chronic granulomatous disease
excessive inflammation granulomas lymphadenopathy hepatosplenomegaly susceptibility to catalase +ve bacteria (Pseudomonas, Listeria, Aspergillus, Candida, E.coli, S. Aureus, Serratia)
Chronic granulomatous disease
Infection with atypical mycobacterium. Normal FBC
IFN gamma receptor deficiency
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
severe chicken pox, disseminated CMV infection
Classical natural killer cell deficiency
Absence NK cells in peripheral blood
GATA2 and MCM4 subtype 1 and 2 abnormality
Classical natural killer cell deficiency
NK cells present in blood but function abnormal
FCGR3A subtype 1 gene abnormality
Functional NK cell deficiency
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
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)
