primary immunodeficiency Flashcards
immunodeficiency diseases
Defects in one or more components of the immune system can lead to serious and often fatal disorders
-some associated with increased autoimmunity
Primary immunodefiency
genetic, congenital disorders
immune system either missing or abnormal
-mainly caused by mutations
-predisposes to infections and tumours
Abnormality in Pri ID
components of innate system
stages of lymphocyte development
responses of mature lymphocytes to antigenic stimulation
congenital disorders
chronic granulomatous disease
Leukocyte adhesion defiency type 1 &2
antibody deficiencies
agammaglobulinemias
X linked
Autosomal recessive
Hypogammaglobulinemia
Defects in T cell activation
proximal TCR signalling defects
wiskott- aldrich syndrome
Neisseria
suspect defect in complement
B cell defects
Encapsulated
Tuberculosis
Th1
Candida,
Infections with staphylococci, gram-negative bacteria, and fungi are associated with reduced number or function of phagocytes.
TH17
mycobacterium tuberculosis
causes lung infection in immunocompetent people.
herpes simplex
Recurrent attacks of cold sores (herpes simplex) or shingles (herpes varicella zoster) may suggest mild immunodeficiency
-associated with stress and sick
T cell dysfunction
Herpesvirus-induced tumours, notably Kaposi sarcoma (human herpesvirus 8 [HHV8]), and non-Hodgkin lymphoma (Epstein-Barr virus [EBV
causes of pri imm deficiency
mutations
polyporphisms
polygenic disorders
mutation
permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people
polymorphisms
different variations of same gene, different allele but still produce functional protein, but still can cause problems
polygenic disorders
These are disorders caused by the combined action of more than one gene.
Polygenic disorders of the immune system are relatively common and affect mainly antibodies.
severe combined immunodeficiency (group of diseases)
affect both T and B cells
die in the first few months of life unless treatment is given
autosomally inherited
Stem cell transplant can cure SCID but it has to be done quickly
screening
types of SCID
defective pre TCR checkpoint
Di George syndrome
Fox N1 deficiency
X linked
polymorphism
- Human leukocyte antigen (HLA) alleles are polymorphic and affect the outcome of infections.
- HLA alleles that are unable to bind viral peptides have a worse outcome.
- Mannan-binding lectin (MBL) is a collagen-like protein that binds sugars in bacterial cell walls and activates the classic complement pathway. Polymorphisms in MBL and complement affect the risk for infections.
polygenic disorders common variable immunodeficiency
requiring treatment and occurs in about 1 in 20,000 young people affecting men and women equally.
low levels of IgG
-recurrent respiratory tract infections.
-pneumococcus orHaemophilusspp. despite normal total IgG.
-autoimmunity common
-consanguinity
Monogenic
T and B cells
autosomal recessive SCID
RAG mutations
severe combined immunodeficiency clinical presdefective
defective T cells and B cells and therefore develop infections in the first few weeks of life.
Unusual or recurrent infection
Diarrhoea
Unusual rashes
History
Family history of neonatal death
Family history of consanguinity
Lymphocyte count
very low total lymphocyte count (less than 1 × 109/L [106/mL]).
Lymphocyte numbers should be measured by flow cytometry.
antibody deficiency
Clinical presentation
Antibody deficiency presents later in life.
Babies are born with maternal immunoglobulin transferred across the placenta.
Some forms of antibody deficiency, such as CVID, do not present until adulthood.
Chronic or recurrent bacterial respiratory infection.
Antibody levels
IgG, IgA, and IgM should be measured.
With low levels of immunoglobulins, causes of secondary immunodeficiency should be excluded.
If total Igs are normal, specific antibodies against Haemophilus spp. and pneumococcus should be measured.
If these tests are all normal, it is important to check no problems are apparent with complement or neutrophil function.
treatment of primary
mild-prophylactic antibiotics
more severe- Ig replacement therapy
Antibodies against a wide range of pathogens
Ig pooled
plasma screened for HIV and hepatitis B and C antibodies
When definite treatment
when SCID confirmed
until definite
-avoding live vaccines
-Prophylaxis against opportunist infections such asPneumocystis jiroveci
T cell deficiency stem cell transplatation
-required in SCID
most successful if it can be done within a few weeks of birth, before the infant has developed any infections.
If this is possible, SCT carries a 90% success rate and is curative.
When SCT is not an option, gene therapy may be attempted.
gene therapy
recombinant technology to correct the genetic defect in the patient’s own stem cells, which can then reconstitute the immune system.
used in patients with SCID for whom no suitable stem cell donor was available.
criteria:
- The genetic mutation for each patient must be identified, and there must be evidence that correcting the mutation will improve his or her condition.
- The transfected gene must confer a proliferation or survival advantage.
- Gene therapy must not cause malignancy. (not near oncogenes)
