Paediatric Immunology 1 Flashcards
What immunodeficiency is invasive Neisseria infection associated with?
- Membrane attack complex deficiency (C5-9, typically presents with recurrent meningicoccal meningitis after age 10, also susceptible to disseminated gonococcal infections)
- Properidin deficiency (poor prognosis)
What immunodeficiencies is MSMD associated with?
- IFN-gamma receptor 1+2, IL12B, IL12RB1, IKBKG
- STAT1 most serious, also get viral
What immunological issues are associated with eczema?
- Wiskott-Aldrich syndrome
- IPEX
- hyper-IgE syndromes
- hypereosinophilia syndromes
- IgA deficiency
- CVID
What immunological issues are associated with oral/nail candidiasis?
- T-cell problems
- CID/SCID
- mucocutaneous candidiasis
- hyper-IgE syndromes
- MSMD
What infections are neonates particularly susceptible to and why?
- Gram negative organisms
- IgM does not cross the placenta
Describe the presentation and findings in X-linked agammaglobulinaemia:
- Bruton tyrosine kinase deficiency
- Presents 6-8 months when maternal Ig levels fall, pneumococcal/Hib sinopulmonary infections
- No B cells
- ALL Ig low/absent unless maternal IgG
- Lymphoid hypoplasia (no LN, tonsils, thymus)
- Poor vaccine response
- susceptible to extracellular bacteria and viruses
What drugs are associated with CVID/IgA deficiency?
- Phenytoin
- d -penicillamine
- gold
- sulfasalazine
- Carbamazepine
Describe the presentation and findings in X-linked hyper-IgM syndrome:
- Class-switch recombination defects=B cells prefer IgM production
- Normal/high IgM and low/absent IgG/A/E
Type 1 X-linked - CD40 ligand Xq26 or NEMO
- sinopulmonary, OM, tonsillitis, PJP
- crypto, verruca, liver disease, malignancy
- NEMO - anhydrotic ectodermal dysplasia
Describe the presentation and findings in X-linked lymphoproliferative/Duncan disease:
- Deficient adhesion molecule on thymocytes, T-cells, NK cells - leads to antibody deficiency + uncontrolled cytotoxic T-cell response to EBV.
- Gene SH2D1A
- Well until EBV (<5yo)
- 50% fulminant/fatal EBV
- 25% (B cell) lymphoma
- 25% acquired hypogammaglobulinaemia/CVID
- 70% dead at 10yo
Which B-cell defects are treated with BMT/stem cell transplant?
- X linked lymphoproliferative disease
- X linked hyper IgM
What screening test can be done for SCID?
- Heel prick T cell lymphopenia
- T-cell receptor recombination excision circles are absent or extremely low - PCR
What other pathogens might you be susceptible to if you have MSMD?
Interferon gamma receptor 1/2 - listeria, salmonella and regular Tb
Interleukin 12 - salmonella (typhi and non-typhi)
What x-ray findings do you expect with ADA-SCID?
- No thymus, pneumonia
- Ribs - rachitic rosary (widened costo-chondral junction ant. ribs, also seen in rickets)
- Other areas chondroosseous dysplasia (iliac apophyses, vertebral bodies)
What cytokines do TH-1 cells secrete?
- IFN-gamma (also IL-2 and tumor necrosis factor-beta)
- cell-mediated immunity (macrophage, IgG)
- phagocyte-dependent inflammation
- kill intracellular organisms e.g. viral
What cytokines do TH-2 cells secrete?
- IL-4, IL-5, and IL-13
- strong antibody responses (including IgE)
- eosinophil accumulation IL-5
- inhibit several functions of phagocytic cells (phagocyte-independent inflammation)
- fight helminthic parasites
- (also IL-6, IL-9, IL-10 but less important)
What do dendritic cells do?
- APC
- CD28:B7 interaction
- activate naive T cells -> clonal expansion and differentiation into effector T cells
What are the markers of NK cells? What do NK cells do?
- CD16 and CD56
- Kill virally infected cells
- Kill some types of tumour cells
What are the clinical features of cartilage hair hypoplasia?
- Amish, RMRP 9p21-p13
- short, pudgy hands; redundant skin
- hyperextensible hands and feet but can’t extend elbows completely
- fine, sparse, light hair and eyebrows- CID (most common) or SCID
- varicella, vaccine disease, vaccinia
What are the clinical features of MHC Class II deficiency?
- HLA-DR, -DQ, and -DP deficiency
- North African descent
- Diarrhoea early infancy with cryptosporidiosis and enteroviral infections (e.g., poliovirus, coxsackievirus)
- herpesviruses, oral candidiasis, bacterial pneumonia, PJP, septicemia
- NO disseminated infection from BCG/GVHD from transfusion.
- normal B cells, low CD4, normal-increased CD8
- no antigen response (usually MHC II on APCs)
- hypogammaglobulinemia
Immunodeficiency with Thrombocytopenia and Eczema is also known as:
Wiskott-Aldrich Syndrome
How do you test for CGD?
Chronic granulomatous disease (CGD) related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex problems
The nitroblue-tetrazolium test is the original and most widely-known test for chronic granulomatous disease. It is negative in CGD.
You can also do the DHR test now which is what we use.
Which cells produce IL-1 and 2?
Macrophages and polymorphs and have a target effect on T/B/NK cells
How might Wiskott-Aldrich syndrome present?
- Male with: eczema, thrombocytopenia (low platelet count), immune deficiency
- prolonged bleeding if circumcised
- bloody diarrhoea
- infections (meningitis, sepsis, pneumonia, OM)
- strep. pneumoniae
- later in life: PJP, EBV malignancy
What lab findings might there be in Wiskott-Aldrich syndrome?
- Thrombocytopenia
- Low/absent isohemagglutinins
- Poor response to polysaccharide immunisation (Prevenar)
- Low IgM, High IgA/IgE, normal IgG
- Low T cells
What infections are you susceptible to if you have a mutation of your NK cells?
- HPV
- treat with antiviral prophylaxis and stem cell transplant
What mutations are implicated in hyper-IgE syndrome?
- STAT3 is Buckley Syndrome/AD form
- DOCK8 or TY2 is AR form
What is the most common immunodeficiency?
- Selective IgA deficiency
- US stats - 0.33% or 1/500
How do we give immunoglobulin replacement therapy and why?
- humoral immune defects
- IVIG (Intragram P) q3-4 weekly or SCIG (Evogam) weekly
- Dose: ~300-600mg/kg/month
- Aim for IgG trough or steady state 7-8g/L
What drugs are associated with hypogammaglobulinaemia?
- Antimalarials
- Captopril
- Glucocorticoids
- Carbamazepine
- Phenytoin
- Sulfasalazine
What genetic disorders are associated with hypogammaglobulinaemia?
- SCID
- Hyper IgM
- Ataxia-telangiectasia
- Monosomy 22
- Trisomy 8, 21
What infections are associated with hypogammaglobulinaemia?
- Congenital toxo, CMV, rubella
- HIV
- EBV
Which vaccinations are T-cell dependent VS T-cell independent?
- T-dependent are protein vaccinations (Tetanus, Diptheria, HiB, Prevenar)
- T-independent are polysaccharide vaccinations (Pneumovax23)
What is the abnormality in Wiskott-Aldrich Syndrome?
- X-linked, defective WASP gene
- defective anti-polysaccharide antibody, impaired T cell activation
- Susceptible to encapsulated extracellular bacteria
How might autoimmune lymphoproliferative syndrome present?
- 1st year of life (definitely symptoms by age 5)
- autoimmune problems
- CNS issues (seizure, headache, encephalopathy)
- lymphadenopathy
- splenomegaly, hepatomegaly (50%)
- malignancies
Lab findings - hypergammaglobulinemia (IgG, IgA), cytopenias due to big spleen, autoimmune anaemia/thrombocytopenia/neutropenia
What does IPEX stand for?
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy
- X linked
Describe the presentation of IPEX:
- Male (X-linked)
- Erythroderma (infants) + Eczema
- Enteropathy with neonatal watery diarrhoea, FTT
- Polyendocrinopathy
- Immune dyresgulation with serious bacterial infections, allergies, autoimmune, lymphadenopathy and splenomegaly
Describe the presentation of SCID:
- Unwell < 3/12
- Persistent diarrhoea, FTT
- Infections - severe common infections, PJP, vaccine associated
- Viral eg. CMV/adeno
- Fungal – persistent thrush
What cytokines do TH17 cells secrete?
- IL-17 A and F, IL-22
- Neutrophil/monocyte activation
- extracellular bacteria and fungi
What role do different TH cells play in cell damage?
- TH-1 autoimmune disease, tissue damage with chronic infection
- TH-2 allergic
- TH-17 organ specific
What different phenotypes are there for SCID and what are the genetic associations?
- T- B+ NK+ IL7 receptor alpha deficiency
- T- B+ NK- X linked/common gamma chain SCID 45% or JAK 3
- T- B- NK+ ADA SCID or RAG 1/2
- T- B- NK- Adenosine deaminase deficiency SCID
What specific immunodeficiencies might you consider in Staphylococcus epidermidis infection?
- Neutropenia
- Leukocyte adhesion defects
What specific underlying issues might you consider in burkholderia cepacia infection?
- Chronic Granulomatous Disease
- Cystic Fibrosis
- Sickle-cell haemoglobinopathies
What is the aetiology of Chédiak-Higashi syndrome?
- Autosomal recessive degranulation problem
- Disordered coalescence of lysosomal granules
- Large granules in multiple tissues
- Responsible gene is CHSI/LYST (regulates granule fusion)
What are the half-lives of different immunoglobulin subtypes?
Ig A - 6 days Ig D - 3 days Ig E - 2 days Ig G - 3 weeks (7-23 days depending on subclass) Ig M - 5 days
What % of normal infants have delayed separation of the cord (3/52 or later) ?
10% of healthy infants can have cord separation at age 3 wk or later
How do leukocyte adhesion deficiencies present?
- Infancy, delayed separation of cord with omphalitis
- recurrent infections skin, mouth, resp, lower GI, genital mucosa
- neutrophilia
- skin infections - large chronic ulcers, minimal inflammation
- gingivitis + tooth loss
How does Chediak-Higashi Syndrome present?
- increased susceptibility to infection
- mild bleeding
- partial oculocutaneous albinism
- progressive peripheral neuropathy
- haemophagocytic lymphohistiocytosis (HLH) in 85%
How does AD Hyper-IgE syndrome present?
- AD form - STAT3 or Buckley Syndrome
- Recurrent severe skin and sinopulmonary infections
- staph. aureus, s. pneumoniae, h. influenzae
- eczema
- mucocutaneous candidiasis
- retained primary teeth
- minimal trauma fractures/scoliosis
- characteristic coarse facies
How does AR Hyper-IgE syndrome present?
- DOCK8 gene
- atopy
- increased viral susceptibility and sepsis
- no MSK/dental, more malignancy
- Recurrent pneumonia without pneumatoceles
- boils, mucocutaneous candidiasis
- neurologic symptoms
Describe the findings in Type 2 hyper IgM syndrome:
Type 2, AICDA Chromosome 12
- Normal/high IgM and low/absent IgG/A/E
- lymphoid hyperplasia, no PJP
- tendency to autoimmune/inflammatory problems
- RX IVIG, early abs
Describe the findings in Type 3 hyper IgM syndrome
- Type 3, CD40 chromosome 20
- Normal/high IgM and low/absent IgG/A/E
- sinopulmonary, OM, tonsillitis, PJP
- crypto, verruca, liver disease, malignancy
- RX IVIG, GCSF, stem cell transplant
