WHAT IS IMMUNODEFICIENCY
i) give four characteristics seen in infections that occur in patients that are immunodeficient
ii) give four examples of these infections
iii) which three things makes infections more likely to be significant to the diagnosis of immunodefic?
i) opportunistic, unusual, unusually severe/not responding to standard therapy, frequent
ii) candida ophalmitis, liver abscess from strep, empyema, viral warts on hands, cold sores
iii) more significant if the infection is verified eg cultured rather than just reported by patient
- organism is identified
- end organ damage has occured
GENERAL CLASSIFICATION OF IMMUNODEFICIENCY
i) what is secondary ID? is it common or rare?
ii) name four causes of secondary ID
iii) what is primary ID? is it common or rare?
iv) what are most PIDs seen as 'new diseases' (2)
i) secondary ID > secondary to another disease process
- very common
ii) caused by extremes of age, malignancy espec myeloma and lymphoma, metabolic (diabtetes), drugs (chemo), HIV
iii) PID is immune defect that is intrinsic to the immune system itself = rare
iv) most PIDs are new diseases as they were fatal before antibiotics and charac has required development in technology
IMMUNOL CLASSIFICATION OF IMMUNODEFIC
i) what type of infections are seen as a result of B cell/antibody deficiency? where in the body do these manifest
ii) what type of infections are seen as a result of T cell ID? what condition is this also seen in?
iii) what is T cell immunodeficiency also known as?
iv) what is seen in innate ID?
i) B cell ID > bacterial infections of the respiratory tract
ii) T cell ID > viral, fungal and mycobacterial infection
- seen in HIV
iii) T cell ID is aka cellular immunodefic
iv) innate ID - variety of mainifestations - dep on problem
OTHER CLASSIFICATION OF IMMUNODEFIC
i) which other cells are affected when there are CD4 T cell defects? why? which group is this more marked in? why?
ii) what is immunodefic affecting both antibod (B cells) and T cells called?
iii) how do many ID syndromes manifest? give two examples of this
i) CD4 defects > B cell defects as T cell help is needed for B cells to mature
- more marked in infants and less marked in adults and they have already matured their B cells
ii) B and T cells = combined immunodefic
iii) many ID manifest with immune dysregulation such as uncontrolled inflammation and autoimmunity
AGEING AND IMMUNITY
i) how does susceptibility to infection and response to vaccination change with age?
ii) what happens to the thymus in later life?
iii) what happens in stem ells to reduce quality and quantity of leucocyte output?
iv) how are T and B receptor diversity, neutrophil func, vaccine response altered?
v) how does self tolerance change with age?
vi) what virus is there seen to be an expanded T cell pool against?
i) greater suscep to infection and reduced response to vaccines
ii) thymic involution accelerates in later life
iii) get telomere shortening in stem cells
v) reduced self tolerance > inflam from protective to damaging
vi) expansion of T cell pool to CMV
AGEING AND IMMUNITY CONTINUED
i) name three other factors that can make elderly more susceptible to infection
ii) name three co morbidities that can reduce immunity
iii) what can be used to reduce risk of VZV in elderly?
i) reduced mobility, undernutrition, impaired wound healing, reduced physiol reserve
ii) COPD, congestive cardiac failure, cancer, depression
iii) tailored immune boost vaccine
B CELL DEFICIENCY
i) what type of infections occur? give an example
ii) what type of Ig is low?
iii) what other infections may be seen?
iv) what do infections typically respond to? give two problems with this treatment
v) what can happen if the infections are left untreated?
vi) name four investigations to do if this is suspected
i) bacterial infection > recurrent pyogenic infections of upper and lower resp tract
ii) low IgG
iii) also see gut infections
iv) infections respond to anti microbials but response may be sub optimal and long courses are required
v) can develop irreversible lung damage = bronchiectasis
vi) do CXR, sputum culture, lung func, check Igs
CAUSES OF ANTIBODY/B CELL DEFICIENCY
i) name a physiological cause
ii) name two secondary causes
iii) name two primary causes
i) transient hypogammaglobulinemia of infancy
ii) secondary = IgG loss (renal nephrotic syndrome or burns)
iii) X linked agammaglobulinemia
- X linked hyper IgM syndrome
TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY
i) what is it? how long does it last for in healthy infants?
ii) what can it be correlated with?
iii) when do infants with antibody deficiency usually present? why?
i) period of relative antibody deficiency around 6 months
- fetus doesnt produce IgG but has IgG from mother which gets exhausted around 6 months and takes some time for own IgG to start to rise
- usually transient at around 6 months
ii) can be correlated with increased infections
iii) antibody defic usually present 3-6 months as until then they are protected by maternal IgG
i) where is the mutation? what is this required for?
ii) what does this mean for B cell maturation?
iii) what three things consequently dont occur?
i) mutation in brutons tyrosine kinase which is required for signal transduction at the pro B stage to allow the B cell to mature
ii) maturation is arrested
ii) no heavy change rearrange, no B cells leave the bone marrow and no Ig production
X LINKED HYPER IGM SYNDROME
i) what molecule is there a deficiency in? what cells is this found on?
ii) what does the syndrome cause in relation to B cells?
iii) which two Ig will be low? which may be normal or raised?
iv) what may the patient present with? at what age? why at this age?
i) deficiency in CD40 ligand found on T cells - required to interact with CD40 on B cells > affinity maturation
ii) B cells cant mature from primary to secondary imm response
iii) low IgG and IgA but high/normal IgM
iv) patient may present with recurrent bacterial infections at 3-6 months as that is when maternal IgG is exhausted
X LINKED HYPER IGM MECHANISM
i) what type of Ig does a naiive B cell have on its surface? what happens when it meets antigen? (2)
ii) what antibodies are produced after B cell has matured? what cell does it need to help this?
iii) which antigen on the T cell is also needed for B cell receptor cross linking? what process cant happen if this isnt present ie in this condition
i) naive B cell has surface IgM
- meets antigen > somatic hypermut and class switch recomb
ii) mature B cell produced IgG > needs T cell help
iii) CD40L on T cell binds CD40 to B cell to allow maturation
- if not present then there is no affinity maturation and there is lots of IgM but cant class switch to IgG
TREATING ANTIBODY DEFICIENCY
i) why does it need to be recognised early?
ii) what can be done about inter current infections?
iii) what is the primary treatment? how often is this given
iv) which drugs can also be given to stop recurrent infections?
i) needs to be recog early to prevent lung damage
ii) agressive treatment
iii) primarily need to replace the immunoglobulin
- use donated plasma and mix lots of different donor IgG together
- needs to be given weekly
iv) can give anti microbials
CELLULAR/T CELL IMMUNODEFICIENCY
i) which cells are deficient?
ii) what cells will also be affected if it is congenital? what is this called? why doesnt this happen in adulthood?
iii) name four hallmarks of this type of ID
iv) what is it clasically secondary to?
v) name three conditions classically seen
i) CD4 cells are deficient
ii) also affects B cells if congenital = combined immunodefic
- doesnt affect adults B cells as they have already produced mature B cells
iii) hallmarks - opportunistic, fungal, viral, mycobac infections
iv) classically secondary to HIV infection
v) candida oesophagus, CMV retinitis, kaposi sarcoma, PCP, toxoplasmosis
SEVERE COMBINED IMMUNODEFICIENCY
i) what is it? which cells are absent? which cells may be present but non functional?
ii) when does it present?
iii) what may cause a rash?
iv) name three two other things that may be seen
v) name three types of infection that may be seen
i) rare and life threatening primary immunodeficiency
- absent T cells
- B cells may be present but non functional
ii) presents soon after birth
iii) can cause a rash due to GvHD - maternal lymphyocytes are not destroyed by fetus and engraft to BM > prod lymphocytes recog as foreign by baby > GVHD
iv) also see chronic diarrhoea and fail to thrive
v) can see bacterial, mycobac (BCG), viral (CMV) and fungal (PCP)
COMMON GAMMA CHAIN DEFICIENCY
i) what does it cause?
ii) common gamma chains form part of which membrane receptors? what can these molecules be responsible for?
iii) which cells are absent? which cells are present but non functional?
iv) what deficiency causes auto recessive SCID? why is this immunol identical to gamma chain defic?
i) causes X linked SCID
ii) common gamma chains form part of membrane receptors for cytokines that are responsible for T cell maturation
iii) T cells are absent and B cells can be present but non functional
iv) JAK-3 deficiency can cause auto recessive SCID
- immunol identical to gamma chain defic as it is downstream of the common gamma chain
RAG 1 AND 2 DEFICIENCY
i) what type of SCID does it cause?
ii) what are RAG1/2 required for? what does deficiency of these enzymes mean?
i) causes auto recessive SCID
ii) RAG1/2 req for somatic recombination events between VDJ gene segments
- deficiency = no T and B cell receptors therefore no adaptive immunity
i) who are stem cells harvested from? give two methods this can be done?
ii) what happens after the stem cells are infused into the patient? (3)
iii) which cells are used in gene therapy?
i) SC from a HLA matched donor
- either by bone marrow sampling or mobilising SC with GM-CSF infections > SC migrate to periph blood > leucophoresis
ii) stem cells to patient > travel to BM > engraft > reconstitution of T and B cells
iii) use stem cells from the patient in gene therapy
DI GEORGE SYNDROME
i) what fails to happen?
ii) name four structures that are affected in the full phenotype
iii) on which chromosome do most patients have microdeletions?
iv) how can it present? what condition is also common?
i) failure of migration of 3rd and 4th brachial arches
ii) absent parathyroids (low calcium/tetany), cleft palate, congenital heart defects, thymic aplasia (low T cell numbers)
iii) microdelet on chromo 22
iv) has very variable presentation from major to minor
- autoimmunity is also common
TERMINAL COMPLEMENT DEFICIENCY
i) what is it?
ii) what specific bacteria is the patient susceptible to?
iii) how is it diagnosed?
i) deficiency of terminal complement components C5-C9
ii) neisseria species > reccurent neisseria menigitis
iii) diagnosed by functional complement assays