16. immunodeficiency diseases

Question 1

what is meant by immunodeficiency?

Answer 1

no definitive definition infections are: opportunistic, unusual, unusually severe, protracted or not responding to standard therapy and frequent

Question 2

secondary immunodeficiency

Answer 2

immune defect is secondary to another disease process

very common

Question 3

causes of secondary immunodeficiency

Answer 3

extremes of age
malignancies (esp myeloma, lymphoma)
metabolic, eg diabetes 
drugs, eg chemotherapy, steroids 
infection, eg HIV

Question 4

primary immuonodeficiency syndrome (PID)

Answer 4

immune defect is intrinsic to immune system itself
rare, often genetic
over 100 characterised
most are fairly ‘new’ - fatal pre-antibiotics

Question 5

antibody deficiency

Answer 5

B cells affected
humoral immunodeficiency
predominately bacterial infections of respiratory tract

Question 6

cellular immunodeficiency

Answer 6

T cells affected

predominately viral, fungal and mycobacterial infections

Question 7

combined immunodeficiency

Answer 7

immunodeficiency syndromes affecting antibody production an dT cells

Question 8

immune dysregulation

Answer 8

uncontrolled inflammation, autoimmune diseases

manifestation of many immunodeficiency syndromes (in addition of infection)

Question 9

predominately antibody deficiency

Answer 9

low IgG - other isotopes may be affected
manifests with recurrent pyogenic infection of upper and lower respiratory tract
sometimes gut/skin infections too
infections rarely respond to antimicrobials - suboptimal/long course required
may lead to irreversible lung damage (bronchiectasis) is untreated

Question 10

physiological cause of antibody deficiency

Answer 10

transient hypogammaglobulinaemia of infancy

Question 11

secondary causes of antibody deficiency

Answer 11

IgG loss

• renal: nephrotic syndrome
• skin: extensive burns

impaired IgG production
- immunosuppressive drugs

Question 12

primary causes of antibody deficiency

Answer 12

x-linked agammagloobulinaemia
x-linked hyper-IgM syndrome
+ many others

Question 13

maturation of antibody production (infants)

Answer 13

normally a period of relative antibody deficiency
around 6 months
physiological state
= transient hypogammaglobulinaemia of infancy
infants with antibody deficiency usually present around 3-6 months (protected by maternal IgG until then)

Question 14

XLA - X-linked agammaglobulinaemia

Answer 14

signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage
maturation arrest occurs if no btk present
XLA - deficiency of btk

Question 15

what happens in B cell maturation arrest?

Answer 15

no heavy chain rearrangements
no B cells leave marrow
no immunoglobulin production

Question 16

X-linked hyper IgM syndrome

Answer 16

CD40L deficiency 
low IgG and IgA
raised/normal IgM
recurrent bacterial infections 
present age 3-6 months 
immunological lesion in T cell 
CD40L - no B cell cross linking, no affinity maturation

Question 17

treating antibody deficiency

Answer 17

early recognition, before long damage occurs
aggressive treatment of intercurrent infections
replace immunoglobulin - passive immunisation
long term suppressive antimicrobials

Question 18

cellular immunodeficiency

Answer 18

CD4 T cell deficiency
when congenital, antibodies also affected
classic secondary cause = HIV

Question 19

cellular immunodeficiency manifestation

Answer 19

opportunistic infection
viral infection
fungal infection
mycobacterial infection

Question 20

severe combined immunodeficiency (SCID)

Answer 20

rare, life threatening primary immunodeficiency
absent T cells
B cells may be present, but non-functional

Question 21

SCID presentation

Answer 21

usually soon after birth
rash (GVH- maternal lymphocyte engraftment)
failure to thrive
chronic diarrhoea
infections - esp opportunistic
bacterial, mycobacterial (esp BCG), viral (CMV, EBV), fungal (PCP, oral thrush)

Question 22

SCID molecular causes

Answer 22

common gamma chain deficiency
JAK-3 deficiency
RAG 1/2 deficiency

Question 23

common gamma chain deficiency

Answer 23

X-linked SCID
common gamma chain forms part of membrane receptor for several cytokines (some required for t cell maturation)
absent t cells
B cells present but non-functional

Question 24

JAK-3 deficiency

Answer 24

autosomal recessive SCID
JAK-3 is downstream of common gamma chain - also prevents signalling
immunologically identical to gamma chain deficiency

Question 25

RAG 1/2 deficiency

Answer 25

autosomal recessive SCID
RAG 1/2 required for somatic recombination events between V(D)J segments
no T or B cell receptors

Question 26

SCID therapy

Answer 26

stem cells harvested from HLA-matched donor
given to  recipient by infusion
engraft in bone marrow
reconstitution of T and B cells 
alternative = gene therapy

Question 27

DiGeorge syndrome

Answer 27

failure of migration of 3rd/4th branchial arches
most patients have micro deletions on chromosome 22
can present with any isolated part of full phenotype

Question 28

DiGeorge syndrome full phenotype

Answer 28

absent parathyroids (low calcium, tetany)
cleft palate
congenital heart defects 
thymic aplasia (low T cell numbers, immunodeficiency)

Question 29

DiGeorge syndrome presentation

Answer 29

variable
huge spectrum fo immunodeficiency: from mild to SCID-like
autoimmunity is common

Question 30

terminal complement deficiency

Answer 30

deficiency of terminal complement components (C5-C9)
susceptible to Neisseria species - esp meningitidis
otherwise immunologically orbust
diagnosis by functional complement assays