Immunology Flashcards
Pancreatic insufficiency, neutropenia, and a
chemotactic defect that may lead to increased
susceptibility to pyogenic infection is associated with
which condition?
Shwachman-Diamond syndrome
• Shwachman-Diamond syndrome is an autosomal
recessive disorder, characterised by neutropenia,
pancreatic insufficiency, skeletal abnormalities
resulting in short stature
• And some children have defects in chemotaxis or in
the number or function of B, T and natural killer cells, thatmay contribute to the increased susceptibility to pyogenic infection.
• 90% result from a mutation in the SBDS gene
What is X-linked agammaglobuliaemia (XLA)
- defect in early B cell lymphocyte development
- This is a severe hypogammaglobulinaemia with absence of circulating B cells
- x linked,
- defect in Butron tyrosine kinase (Btk) which is involved in B-cell signal transduction pathway leading to arrest at the PreB cell stage
- low IgG <0.2, low IgM and IgA
- small or absent tonsils
- no palpable lymph nodes
- poor or absent response to vaccines
- complete lack of antibodies in their bloodstream
- CD19 + B cells <2% of total lymphocyte count
- onset infections occur at 3-6/12, majority recurring infections <2years age
Boys are well during first 6-9 months (due to maternally transmitted IgG), then they get infections (Strep pneumoniae, H.influenza unless prophylactic antibiotics or Ig therapy). Sinusitis, OM, pneumonia, meningitis and sepsis less common.
Diagnosis is by: lymphoid hypoplasia - minimal or no tonsillar tissue, no palp LN; serum IgG, IgA, IgM, IgE far below range for age; total Ig < 100mg/dL. Levels of Ab to Ag given in routine immunisations abnormally low (whereas transient in hyopgammaglobulinaemia of infancy).
Flow cytometry – shows absence circulating B cells (distinguishes from transient hypogammaglobulinaemia of infancy).
-Btk mutation gene analysis
Treatment is with IVIG 3-4 weekly
What is a class switch recombination defect?
- Failure from class switch IgM to IgA and IgG
- majority are CD40L deficiency (70%)
- x linked
- high IgM but low A, G and E
- 3 groups of disorders
1. Defective CD40L-CD40 interaction
2. Defect in CD40 mediated NF-kB activation (NEMO gene mutation)
3. Defects initiating double stranded DNA breaks in process of class switch recombination (AID and UNG deficiency)
What is CD40L deficiency?
Hyper IgM syndrome
Most common class switch recombination defect
- aka x-linked hyper IgM syndrome
- note that CD40L induces class switch by binding of CD40L on activated T CELLS and CD40L on B cells
- leads to both CELLULAR and HUMORAL immunodeficiency
- most present <2 years of age
- present with recurrent sinopulmonary infections from encapsulated bacteria
- get PCP
- Cryptosporidium enteritis and sclerosing cholangitis
- viral infections esp HSV, CMV, parvo B19
- mycobacterium
- if neutropenia can get pyogenic or fungal infections
IPEX syndrome
- immunodysregulation polyendocrinopathy enteropathy X-linked
- syndrome is a rare disease linked to the dysfunction of the transcription factor FOXP3
- FOXP3 is widely considered to be the master regulator of the regulatory T cell lineage. I
- It leads to the dysfunction of regulatory T-cells and the subsequent autoimmunity
- Also at risk of diabetes and other autoimmune mediated disease such as early onset (and aggressive) IBD
behcets disease
small and medium sized vessel vasculitis
etiology unknown
associated with HLA-B5 and HLA-B51 –> likely autoimmune
Multisystem disorder- usually recurrent oral and genital ulcers with relapsing iritis or uveitis
Cutaneous, neurological, arthritic, vascular and GI manifestations
Vasculitis can affect aortic and pulmonary artery
Can get Budd chiari syndome (inflammation and thrombosis of SVC or IVC cuasing portal HTN)
5% cases are children
DDX
HSV, IBD
Recurrent aphthous ulcer stomatitis
Complex apthosis (oral and genital apthous ulcers)
Rx:
CCS
Colchicine (best in children)
Azathioprine, cyclosporine, tacrolimus
Autoimmune hepatitis
Primarily hepatocyte process (unless associated with IBD or primary sclerosing cholangitis)
Type1: Less severe than type 2 ANA and SMA +ve in 50% of kids with type 1 Most common type Occurs at any age 75% female Responds well to Rx usually Variable risk relapse
Type 2: Most severe Liver kidney microsome (LKM) +ve in large proportion with type 2 Often age 10-20 years old 95% female Frequent Rx failure and relapse
Sx both:
Wide range, may present primarily liver disease or extrahepatic
Malaise, fatigue, weight loss, cirrhosis, portal HTN
Liver may be big or normal
Big spleen common
Raised ALT, AST. May have slightly raised GGT, ALP often normal
Low albumin
Raised total protein (cos raised gammaglobulin)
Rx:
- Steroid
- Azathioprine +/- ccs
- Mycophenalate motifil
X-linked aggamaglobulinemia and infection
Patients often have neutropaenia at height of acute infection.
Clinically, patients are usually well for the first 6-9 months of life because of maternally transmitted IgG antibodies; then acquire infections with extracellular pyogenic organisms e.g. Strep pneumonia, H.influenzae, unless given prophylactic antibiotics or immunoglobulin therapy.
- Infections: sinusitis, OM, pneumonia,
- Mycoplasma infections are also problematic
- Less often: sepsis, meningitis
- Chronic fungal infections can also be seen
- PCP pneumonia rarely occurs
- Viral infections usually handled normally except hepatitis and enteroviruses
Vaccination protection
- BCG. Vaccine protection lasts 10-15 years
- DTP. Pertussis antibody wanes after 3-5 years, not measurable after 12 years.
- HiB. Vaccine will last until the child is at least 5 years old.
- Hep B. Despite some decline in anti-HBs titres with time, most vaccinated people remain protected against HBV infection.
- Pneumococcal polysaccharide. Immunologic responsiveness and efficacy is unpredictable in children < 2yrs age.
SCID
Most severe immunodeficiency
Lack/Low B and T cells
- mutation in component crucial for lymphoid tissue development –> lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes
- IL2RG crucial for signal transduction in B and T cell receptors
- very small thymus that usually fail to descend from neck
- LN, tonsils, adenoids and peyer patches are very small or absent
- Lymphopenia <2.5 at birth (If have T cells, usually maternal)
- Present in first few months of life with recurrent/persistent diarrhoea, pneumonia, otitis media, sepsis, cutaneous infections
- FTT and wasting after infections start
- Opportunistic infection
- -> candida
- -> PCP
- -> VZV, measles, CMV, EBV, adenovirus, BCG
- -> leads to death
- cannot reject foreign tissue so at risk of GvHD from maternal T cells crossing placenta, T lymphocytes from non-irradiated blood products or allogenic SCT
Rx:
Emergency
Needs SCT or will likely die within first year of life. If Dx before 3.5 months can have HLA-identical or T cell depleted haploidentical (half matched) SCT from parents
Hyper IgM syndrome
- Most cases are caused by mutations in a gene that is located on the X chromosome
- Gene encodes a protein (CD40 ligand) on the surfaces of activated helper T cells.
-In the presence of cytokines, normal CD40 ligand interacts with B cells and thus signals them to switch from producing IgM to producing IgA, IgG, or IgE.
- In X-linked hyper-IgM syndrome, T cells lack functional CD40 ligand and cannot signal B cells to switch.
Thus, B cells produce only IgM
- IgM levels may be normal or elevated.
- may have severe neutropenia and often present during infancy with Pneumocystis jirovecii pneumonia.
- Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 yr of life.
Transient hypogammaglobulinaemia of infancy
-THI is characterised by decreased serum IgG with or without decreased IgA and IgM in infants older than 6 months of age in the first years of life, but with normal to near-normal antibody responses to protein immunisations
Interleukins
Th1 cells produce IFN-gamma, IL-2
Th2 cells produce IL4,5,6,13,21
Hyper IgE syndrome
Very high IgE (1000s), impaired neutrophil locomotion. Clinical features include: eczema infections, staphylococcal abscesses of lung, skin, joints. Treatment is with prophylactic antibiotics, IVIG, abscess drainage
CVID
This is a hypogammaglobulinaemia with phenotypically normal B cells.
- occurs in patients with family members with IgA def
- usually sporadic or AD
- T cells usually normal but can have depressed function
- low IgG, IgM, IgA
Infections are similar to XLA but less severe. Equal sex distribution (unlike XLA).
Clinical features: normal or enlarged tonsils, lymph nodes; splenomegaly ~ 25% patients.
- increased risk of lymphoma
Treatment is with immunoglobulin replacement.
