1y immunodeficiency Flashcards
immune cell development
pluripotent stem cells differentiate into different types of immune cells (thymus/bone marrow) –> pre myeloid, lymphocyte committed stem cells, pre monocyte cells
pre myeloid - precursor for neutrophils
lymphocyte committed stem cells - precursors for T and B cells
pre monocyte cells - develop into monocytes and macrophages
what are the different types of T cells
effector and suppressor T cells
CD4 - Th1, Th2, Th17, regulatory T cells
regulatory CD8 cells
what are B cells responsible for
producing antibodies
once they start secreting antibodies they become plasma cells
what are the 2 types of immune responses
specific vs non specific
what defence is involved in specific immunity
antibody - plasma cells
cellular immunity - T cells and APCs
what defence is involved in non-specific immunity
complement
phagocytes
what usual organisms are isolated in antibody defence
pyogenic bacteria - staphylococci, streptococcus pnuemoniae, haemophilus influenzae
some viruses: enteroviruses - polio, ECHO
what usual organisms are isolated in cellular immunity defences
viruses - cytomegalovirus, herpes zoster, measles, papilloma
fungi - candida, aspergillus, pneumocystis
bacteria - myobacteria, listeria
protozoa - cryptosporidium
what usual organisms are isolated in complement defence
pyogenic bacteria
neisseria
what usual organisms are isolated in phagocyte defence
bacteria - staphylococci, gram -ve
fungi - aspergillus, candida
which is more specific: innate or adaptive immunity
adaptive
serum immunoglobulin levels through life (pre-natal to 10yrs)
for the 1st 6mths of life the main source of antibodies are the maternal antibodies that pass through the placenta
babies gradually start building their own antibodies with age
what does immunodeficiency mean
defects in any one or more components of the immune system
can lead to serious and often fatal disorders
collectively known as immunodeficiency diseases
why is the immune system important
integrity of the immune system is essential for defence against infectious organisms and their toxic products
classes of immunodeficiency diseases
1y or congenital
2y or acquired
what is the major consequence of immunodeficiency
other consequences
increased susceptibility to infection
also susceptible to certain types of cancer
certain immunodeficiencies are associated w/ an increased incidence of autoimmunity
what causes 1y immunodeficiency
genetic, congenital disorders - mainly caused by genetic aberrations
small number caused by autoimmunity
part of the immune system is missing/functioning abnormally
not 2y to other disease processes, toxins or drugs
what does 1y immunodeficiency predispose to
infections
tumours
where can the abnormality be in 1y immunodeficiency
components of the innate immune system
stages of lymphocyte development
responses of mature lymphocytes to antigenic stimulation
when to suspect immune deficiency
children - more than 3-4 infections each year or unusual infections or difficult to treat infections
adults - more frequent infections, more severe infection
defects in lymphocytes in 1y immunodeficiency
can happen at any level
the earlier the defect is in the process of development, the more severe the disease
what happens if there is a defect in TCR signalling
T cell receptor signalling
defect in antigen presentation, processing and recognitiion
defect in immune response
what does the increased susceptibility to infection in immunodeficiency depend on
the component of the immune system that is defective
indicates which infection the patient will be more susceptible to
what does the type of opportunistic infection present give us a clue to
degree and cause of immunodeficiency
what would repeated infection w/ encapsulated bacteria indicate
defective antibody production
mild immunodeficiency
what can antibody deficiency result in
IgG and IgA deficiency
can lead to recurrent resp infection
pneumococcus/haemophilus spp
what are infections w/ staphylococci/gram -ve bacteria/fungi associated w/
reduced number/function of phagocytes
what can complement defects predispose to
neisseria infection and encapsulated bacteria
what can defects in T cells or macrophages predispose to
infection w/ intracellular organisms - protozoa, viruses and intracellular bacteria
incl mycobacteria
T cell immunodeficiency and mycobacterial infection
- severity of immunodeficiency
- infection
severity of T cell immunodeficiency is reflected in patterns of mycobacterial infection
in mild T cell immunodeficiency it is able to invade the body outside the lungs
more severe immunodeficiency predisposes to widespread infection w/ mycobacteria of low virulence normally found in the environment
what is mycobacterium tuberculosis
virulent organism
causes lung infection in immunocompetent people
what is reactivation of latent herpes infection linked to
T cell immunodeficiency
recurrent attacks of coldsores (HSV) or shingles (HZV) may suggest mild immunodeficiency
what is recurrent candida infection suggestive of
defects in the Th17 pathway
examples of viral induced tumours
what are they characteristic of
herpes virus induced tumours - Kaposi sarcome (HHV8)
non-Hodgkin lymphoma - EBV
T cell dysfunction
3 causes of 1y immunodeficiency
mutations
polymorphisms
polygenic disorders
what is a mutation
permanent alteration in the DNA sequence that makes up a gene - the sequence differs from what is found in most people
mutations affecting the immune system are rare, can affect any part of the immune system and cause severe disease
what are polymorphisms
involves one of two or more variants of a particular DNA sequence - aka alleles of the same gene occurring at a single locus in at least 1% of the pop
most common polymorphism involves variation at a single base pair
can also be much larger in size and involve long stretches of DNA
polymorphisms in the immune system
common traits that affect any part of the immune system and cause a moderate increased risk for infection
not usually as severe as diseases associated w/ mutations
what are polygenic disorders
disorders caused by the combined action of more than one gene
polygenic disorders of the immune system
relatively common disorders of the immune system and affect mainly antibodies
some of these polygenic conditions may be caused by autoimmunity
what condition do many mutations result in
severe combined immunodeficiency (SCID)
what is SCID
group of disorders that affect both T and B cells
prognosis of SCID
infants die within the first few mths of life unless treatment is given
genetics of SCID
some are autosomally inherited and there may be a hx of consanguinity
other types are X linked and there may be a hx of early deaths in maternal uncles
treatment for SCID
stem cell transplant can be a cure - has to be done quickly
if performed very soon after birth 90% survive
if delayed for a few mths - 50% survive
many countries screen for SCID in newborns
what can polymorphisms result in
human leukocyte antigen (HLA) alleles are polymorphic and affect the outcome of infections
polymorphisms in mannan-binding lectin (MBL) and complement affect the risk for infections
impact of non-functioning HLA alleles
individuals w/ HLA alleles that are unable to bind viral peptides have a worse outcome
what is MBL
collagen-like protein that binds sugars in bacterial cell walls and activates the classic complement pathway
examples of polygenic disorders
common variable immunodeficiency (CVID)
IgA deficiency
specific antibody deficiency
- relatively common polygenic disorders that affect antibody production
how common is CVID
most common 1y immunodeficiency requiring treatment
occurs in ~1/20 000 young people
M+F
immune features of CVID
low levels of total IgG
IgA, IgM levels and B/T cell numbers are variable
clinical features of CVID
recurrent resp tract infections
gut, skin and nervous system infections
autoimmunity is common
many pts have hx of other affected family members or of consanguinity - autosomal recessive inheritance
what happens to pts w/ specific antibody deficiency
recurrent infections w/ pneumococcus/haemophilus spp despite normal total IgG
don’t respond to polysaccharide agents and have poor titres of antibodies to pneumococcal antigens even after vaccination
example of 1y immunodeficiency caused by autoimmunity - polygenic
pts w/ autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) frequently experience severe recurrent candida infection
- defect in central tolerance and experience many types of autoimmunity
what differences in immune system do pts w/ APECED have
some pts w/ APECED produce antibodies against IL-17 –> impaired responses to candidiasis
other individuals who have no genetic defects produce antibodies against IFN-gamma
- recurrent problems w/ mycobacterial infection
autosomal recessive SCID
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
T and B cells
recombinase (RAG) mutations
all pathogens
Wiskott-Aldrich syndrome
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
T and B cells
actin cytoskeleton
all pathogens
X-linked SCID
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
T and NK cells reduced, B cells not functional
cytokine receptor common gamma chain
all pathogens
DiGeorge syndrome
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
T cells
absent thymus
intracellular pathogens
anti-IL-17
- genetics
- cell/pathway
- defect
- main type of infection
autoantibodies
T cells
TH17 responses
candida
anti -IFN gamma
- genetics
- cell/pathway
- defect
- main type of infection
autoantibodies
T cells
Th1 responses
mycobacteria
hyper IgM syndrome
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
B cells
mutations in CD154
pneumococcus and haemophilus
X-linked antibody deficiency
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
B cells
mutations in BTK
pneumococcus and haemophilus
CVID
- genetics
- cell/pathway
- defect
- main type of infection
polygenic
B cells
unknown defect
pneumococcus and haemophilus
IgA deficiency
- genetics
- cell/pathway
- defect
- main type of infection
polygenic
B cells
unknown defect
pneumococcus and haemophilus
specific antibody deficiency
- genetics
- cell/pathway
- defect
- main type of infection
polygenic
B cells
unknown defect
pneumococcus and haemophilus
TAP defects
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
antigen presentation
impaired antigen processing
all pathogens
HLA
- genetics
- cell/pathway
- defect
- main type of infection
polymorphisms
antigen presentation
viruses
complement deficiency
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
complement
membrane attack complex
bacteria - esp Neisseria
MBL
- genetics
- cell/pathway
- defect
- main type of infection
polymorphisms
complement cascade
many pathogens
chronic granulomatous disease
- genetics
- cell/pathway
- defect
- main type of infection
monogenic
phagocytes
oxidative burst
staphylococci and invasive fungi
diagnosis - clinical presentation of SCID
children - defective T cells and B cells, develop infections in the first few wks of life
unusual/recurrent infection
diarrhoea
unusual rashes
diagnosis - SCID hx
FHx neonatal death
FHx consanguinity
diagnosis - SCID lymphocyte count
very low total lymphocyte count - <1x10^9/L
lymphocyte numbers should be measured by flow cytometry
diagnosis - clinical presentation of antibody deficiency
presents later in life
some forms e.g. CVID don’t present until adulthood
chronic/recurrent bacterial resp infection
diagnosis - antibody levels in antibody deficiency
measure IgG, IgA, IgM
w/ low levels of immunoglobulins, causes of 2y immunodeficiency should be excluded
if total Igs are normal, measure specific antibodies against haemophilus and pneumococcus
if these tests are all normal, it is important to check no problems are apparent w/ complement/neutrophil function
aim of treatment of 1y immunodeficiency
prevent infection
treatment of 1y immunodeficiency
mild immunodeficiency - prophylactic abx may be adequate
more severe antibody deficiency - immunoglobulin replacement therapy
what is immunoglobulin therapy
antibodies against a wide range of pathogens
Ig pooled from thousands of normal donors
Ig replacement can be given IV or SC
plasma screened for HIV, hep B and C antibodies
treatment of SCID
if confirmed - definitive treatment
until definitive treatment, avoid serious infection
stem cell transplant for SCID and most T cell deficencies
steps to avoid serious infection in SCID
avoid live vaccines - MMR, polio
prophylaxis against opportunist infections e.g. pneumocystis jiroveci
stem cell transplants
most successful if done within wks of birth before the infant has developed any infection
- if this is possible, 90% success rate and curative
when SCT isn’t an option - attempt gene therapy
gene therapy for 1y immunodeficiency
uses recombinant technology to correct the genetic defect in the pts own stem cells which can then reconstitute the immune system
used in pts w/ SCID for whom no suitable stem cell donor was available
what criteria must be met for gene therapy to be successful
- genetic mutation for each pt must be identified and there must be evidence that correcting the mutation will improve the condition
- transfected gene must confer a proliferation/survival advantage
- gene therapy mustn’t cause malignancy
gene therapy in X linked SCID
