immunodeficiency Flashcards
what is the main function of the immune system?
to protect from infection
what is required in order to protect from infection?
recognise pathogens, mount immune response (need cell to cell communication), clear pathogen which may require adaptive, and self regulation to minimise host damage
what are the characteristics of innate immunity?
same response everytime - use generic molecules and no memory - barriers, pathogen recognition, cellular are complement, rapid onset, does not alter on repeated exposure
what are the characteristics of adaptive immunity?
it is antigen specific and therefore will recognise particular molecules - slower. This can be induced through vaccination, and then the second time exposed to bug it is more robust through memory
what are the types of innate immune response?
barriers and chemical mechanisms, cellular (natural killer and phagocytes), complement and pathogen recognition
what are types of adaptive immune response?
`humoral (ABs and B cells) and cellular (B and T cells)
what is immunodeficiency and what is the more common type?
when the immune system cannot protect itself / is not effective enough to protect body against infection as it is not functioning properly. Secondary dysfunction is more common
what is primary immunodeficiency?
an inherent defect within the immune system that is generally genetic
what is secondary immunodeficiency?
when the immune system is affected due to external causes e.g. HIV
what are some causes of secondary immunodeficiency?
breakdown in physical barriers - CF
protein loss - protein losing enteropathy, malnutrition and burns
drugs - DMARS, steroids, myelosupressives, anti-convulants, rituximab
infection - HIV and TB
malignancy - lymphoproliferative disease and myeloma
how can CF causes secondary immunodeficiency?
mucus accumulation along with other physical manifestations resulting in not being able to clear so more infection pone and protein and Ig losing
what do myelosupressives do?
they knock out the bone marrow so affect the production of B cells
why does blood cancer result in secondary immunodeficiency?
the cloning of cells in the immune system and takes up space
what are the two main cells in innate immunity?
macrophages - long lived
neutrophils - short lived
what is the basis of defects in innate immunity?
diseases associated with removing the dead bacteria once they have been phagocytosed
what do pathogen recognition receptors do?
they recognised conserved pathogen associated molecular patterns which are unique to each pathogen and ensure do not react to self antigen resulting in tolerance
what is an example of PAMP and what recognises it?
lipopolysaccharide and TLR4 (toll like receptor) recognises LPS which tend to repeat sequences
where are PAMPS?
they are on pathogenic cells not host cells
what do phagocytes use to recognise pathogens?
PRRs
what is TLR3 and 5?
without TLR3 we cannot recognise and get rid of viruses, TLR5 is found on some bacteria - flagellin
what is the process of PRR?
the receptor recognises, the cascade leads to interferon and cytokine release resulting in an immune response
what defects lead to a cell being prone to infection?
defects in IRAK4 and MyD88
what is the cell wall of LPS made of?
there is the outer and inner membrane and inbetween there is peptidoglycan
what is the LPS made of?
Lipid A, core, O-polysaccharide
what are clinical presentations of immune response?
pneumococcus will show consolidation on CXR, raised CRP in infection indicates inflammation
why may an individual not feel unwell?
if cytokines are not being released or in a poor inflammatory response where CRP is not raised
how would a poor immune response be detected?
normal levels of Igs, lymphocytes and neutrophils
how will an IRAK4 deficiency present?
recurrent bacterial infection (especially streptococcus and staphylococcus) - pneumonia, meningitis and arthritis, poor inflammatory response, susceptibility to infection increasing with age - similar presentation to MyD88
how would you treat IRAK4 deficiency?
prophylactic antibiotics - IV Ig if severe
what will happen if there is a defect in TLR3?
it is for viral RNA and therefore will lead to recurrent HSV encephalitis
what are MyD88 and IRAK4 involved in?
inflammatory cascade
how does the phagolysosome work?
NADPH in the phagolysosome is made up of several proteins that releases electrons to produce bleach (hypochlorous acid) to kill bacteria
what is an example of a protein in NADPH?
gp91(phox) that is encoded by the X chromosome
what is the process of making hypochlorous acid?
oxygen and a free electron released from the proteins makes O2- (superoxide) which then makes hypochlorous acid
what is a granuloma?
a collection of macrophages
what will reduced DHR show in CDG patient?
the PMA activated neutrophils will rise to higher percentage of maximum at same time as resting neutrophils rather than after
what is CDG?
chronic granulomatous disease that is X linked. It results in recurrent abscesses in the lung, liver, gut, skin and bone and will show normal lymphocytes, neutrophils and Igs in investigations. It is due to unusual organisms such as aspergillus in lungs resulting in ball of fungus and air around the fungus. It could also be from staphylococcus, Klebsiella, Serretia or fungi
how would you treat CGD?
haemopoeitic stem cell transplant and Antibiotics
how does the test of function of macrophages work in CGD?
test the reduction (gain of electron) - measure dihydrohodamine reduction using flow cytometry or in blood - eceltrons released and neutrophil activated by PMA
what would happen in a healthy nitro blue tetrazolium dye?
reduction - healthy neutrophils go purple when reduced
what is in the complement system and what are they for?
non Ig proteins for cell lysis, control of inflammation and stimulation of phagocytosis - sequence of events activates the complement proteins - complement should lyse cells if they are covered in antibodies and will trigger the classical pathway
how would you tests the complement system?
dilute serum at different concentrations - a patients serum should lyse a sheep erythrocyte
how is the membrane attack complex formed?
through the classical pathway: microbe attaches to C1 and activates it which change C2 and C4 into C2a and C4b. This means C3 makes C3b which activates C5 to C5b, which combines with C6,7,8,9 to make MAC
through the alternative pathway: factor B, D and P make C5 through polysaccharides on surface of microbe and C3, which then makes C5b using C4b and C3b and combines with C6,7,8,9 to make MAC
what are C3a, C4a C5a used for?
release of histamine from mast cells, dilation of arterioles and chemotaxis of phagocytes
what is C3b used for?
opsonisation
what is the MAC used for?
cytosis of microbe
when does complement deficiency present?
at a young age
what does a C2 and C4 deficiency result in?
infections, SLE and myositis
what does a C5-9 deficiency result in?
repeated bacterial meningitis particularly from neisseria menigitidis
how is the MAC formed?
C5b binds to C7 and 7 which then bind to membranes via C7. C8 then binds to complex and inserts on membrane and C9 molecules bind to complex and polymerise. 1-16 molecules of C9 will bind to form a pore in membrane that is 15nm tall, 10nm wide and 3nm across
what are defects in adaptive immunity?
usually the APC presents the antigen to the B cell through the receptor which binds and then will present to T cell via MHC. The T and B cells are activated. In adaptive immunity defects there is a defect in antibody making
what does the T cell produce once the antigen is presented via the MHC from B cell?
produces cytokines that affect B cells and recruitment of other cells and makes various other types - T helper 1,2,9 and 17
what is primary AB deficiency?
usually presents quite young with recurrent hospital admissions from pneumonia, bronchiecstasis and sinusitis. The blood tests will show normal T cells but no B cells, IgG, A or M and CT may shows signs of recent pneumonia and bronchial thickening
how is X linked agammaglobulinaemia confirmed?
by genetics - defect in Bruton’s tyrosine kinase - needed for B cell signalling and maturation - B cells maturation in bone marrow does not occur so not ABs and B cells are not in the periphery
how can binding of antibodies to antigens inactivate antigens?
neutralisation (blocks viral binding sites and coats bacteria), agglutination of microbes, precipitation of dissolved antigens (all of which enhance phagocytosis) and activation of the complement system leading to cell lysis
what is the bone marrow and periphery?
primary haematopoeitic tissue in the BM and secondary lymphoid organs in the periphery
what are other B cell defects?
CVID, IgA deficiency, C linked hyper IgM syndrome, transient hypogammaglobulinaemia, loss of antibody secretion
what is IgA deficiency?
it is common - 1 in 200 people - more common in caucasian population - presents as recurrent chest infections and higher risk of autoimmune disease but some are completely well as not essential
what is transient hypogammaglobulinaemia of infancy?
when there are no antibodies when baby born - do not start until around 5 months of life when IgG is transferred from mother to child
what does loss of antibody secretion lead to?
recurrent bacterial infection from pyogenic organisms
how would you treat B cell defects?
antibiotics and then IV IgG for life
when do secondary AB deficiency occur?
history of autoimmune disease such as RA or asthma - methotrexate, infliximab, rituximab, gold or sulfasalazine - secondary to drugs is comparatively common
what do investigations of secondary AB deficiency show?
low B, T cells and IgG and IgA
how will secondary AB deficiency present?
no infections most of adult life but a few year history of recurrent bacterial infections - course of ABs over winter period
what does rituximab do?
kills B cells and therefore low or no ABs
what do ABs commonly target?
surface molecule CD20
what is the treatment for secondary AB deficiency?
IgG replacement (usually comes from blood serum) and antibiotics
what is SCID?
severe combined immunodeficiency
how will SCID present?
siblings are ill a lot or have died young, severe oral candida so cannot eat or swallow, complications such as pneumonitis, fulimant disease, meningitis or haemorrhagic lesions, severe infection
what is a risk factor for autosomal recessive conditions?
consanguinity
what will investigations of SCID show?
normal IgG for first 6 months from mother, no T cells, no IgA and reduced IgM, no NK cells but present B cells
what is the treatment of SCID?
paediatric emergency - antibiotics, antivirals and antifungals, asepsis and haemopoietic stem cell transplant - screen
what are the causes of SCID?
if there is a missing chain then will not function, loss of communication between B and T cells and build up of metabolites in blood are toxic to lymphocytes
why are defects in T cells more severe than in B cells?
B cells also need T cell help and therefore cannot function without so the whole adaptive immune system is basically non functional
how would defects in T cells present
recurrent infection with opportunistic infections, bacteria and viruses
what pathogens are common in defects in T cells?
fungi - candida and protozoa - pneumocystis which is pathopneumonic with HIV
what are types of T cell defects?
SCID and DOCK8 deficiency
