Immune deficiency and immunosuppression Flashcards
What can immunodeficiency be defined as?
Repeated, serious infections with bacterial, viral and fungal pathogens, or life-threatening infection with commensal or non-pathogenic free-living bacteria, fungi or protozoan parasites (HIV/AIDs, pneumocystitis pneumonia, candida albicans, TB)
What is immunodeficiency implicated in?
- HIV/AIDS
- Cancer chemo
- chronic granulomatous disease/ leukocytes adhesion deficiency
- transplantations
- therapeutic antibodies - alemtuzumab (anti-CD52)
- mycobacterial infections - HIV+TB, HIV+MAI
Describe T cell deficiencies
Causes susceptibility to infections by viruses and facultative intracellular pathogens, since T roles play integral role in coordinating whole immune response
Also increased risk of developing certain tumours (eg. lymphoma) as impaired T cell immunity curtails the detection of malignant cells
May be inherited or acquired
Describe inherited T cell deficiencies
Thymic aplasia, a.k.a diGeorge syndrome, results in a lack of T cells:
Deletion of a small piece of chromosome 22
CATCH – cardiac abnormalities, abnormal facial expressisons, thymic aplasia (defective development/absence), cleft palate, hypocalcaemia/hypoparathyroidism
Absence of hypoparathyroid glands causes low serum calcium
Describe aquired T cell deficiency
HIV causes a loss of CD4+ T cells
Loss through pyroptosis of abortively-infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ cells by CD8+ CTLs
Results in AIDS – increased risk of common and opportunistic infections
Also → pregnancy and dance age decrease T cell function
Describe B cell deficiencies
Causes susceptibility to pyogenic infections (involving or relating to the production of pus)
Inherited – agammaglobulinaemia:
Mutation in b-cell cytoplamic tyrosne kinase gene (Btk has signalling effect on BCR) which prevents mature B cell production and so causes reduced antibody production in the serum
low conc of antibodies in the blood
X-linked disorder, so much more common in males
Describe deficiencies in the innate immune system
- susceptibility to pyogenic infections Cellular defects (eg. involving PMN) – of macrophages/monocytes or granulocytes
Deficiencies of secreted molecules (eg. a complement component) – prevents MAC formation
Describe chronic granulomatous disease
Results from a defect in NADPH oxidase – prevents the formation of superoxide radical in oxygen burst, so prevents formation of H2O2 and bactericidal oxidants in phagosomes
Failure to clear bacterial infections – pneuomonia, abscesses, septic arthritis, skin lesions, osteomyelitis
Infections with catalase-positive organisms -S.aureus and fungus Aspergillus sp. are most frequent
Frequent development of granulomata - can be obstructive
Diagnosed in early childhood, more common in boys – X-linked subunit of NADPH oxidase
Prophylactic antibiotics, or in serious cases bone marrow transplantation (BMT)
Describe Chediak-Higashi syndrome
Arises from a mutation of a lysosomal trafficking regulator protein → decrease in phagocytosis (less materials trafficked to the lysosome)
Characterised by large lysosomes in PMN
Leads to recurrent pyogenic infections, albinism and peripheral neuropathy
Treatment of immunodeficiency
Treatment with replacement therapy (eg. give immunoglobulins)
Bone-marrow transplantation
Chemotherapy (eg. in AIDS)
Define allograft, xenograft and isograft
- Autograft - self
- isograft - genetically 3. identical individual
allograft - genetically different individuals - xenograft - different species
What are the 3 types of rejection?
Hyperacute
Acute
Chronic
Describe hyperacute rejection
Hyperacute mediated by pre-existing antibodies against transplant antigens (e.g. Blood Group Antigens - ABO [expressed on erythrocytes and endothelial cells], or Rhesus Factor [haemolytic disease of the newborn], or against xenograft antigens such as alpha-1,3-GAL sugars (on porcine cells), either innate or acquired through previous exposures.
Antibodies here bind antigens and activate complement. Leads to platelet coagulation and fibrin clot formation, as well as PMN and monocyte infiltration, and ischemic necrosis of the graft within 18-24hrs. This has been eliminated as the result of routine pre-operative cross-matching.
Describe acute rejection
- based on recognition of tissues as foreign due to MHC differences
- another contribution is made by minor histocompatibility antigens
Describe chronic rejection
Chronic occurs months-years after transplantation, even in the setting of continued immunosuppression. Chronic rejection is characterized by fibrosis and distortion of the normal cellular architecture of the organ and especially of its vessels –> leads to ischemia and loss of function (and need for graft replacement). Incidence increaes with time after transplant (40% for heart by 5 years) but varies between organs (5% for liver at 5 years)
What antigens may activate the immune system against allograft?
both major and minor histocompatibility antigens
1. MHC → encodes the human leukocytes antigens (HLA) )> polymorphic molecules responsible fo eliciting the strongest responses the allogeneic tissues
2. Minor H antigens →proteins that are expressed in some individuals in the population but not others → potential antigenic differences between donors and recipients
Minor = any non-MHC gene that encodes epitopes capable of binding to both MHCU and MHC II molecules and capable of inducing T cel responses
Discuss rejection in athymic patients, e.g. DiGeorge syndrome
Rejection mediated by T cells - Athymic patients such as in DiGeorge Syndrome (thymic aplasia and do not mature T cells) do not display acute rejection, whereas antibody deficient bursectomized chickens or children with agammaglobulinemic do react acutely to allografts.
Describe graft-versus-host disease
- T cells of the donor’s immune system which remain in the graft recognise the host as foreign
- attack the recipient’s body cells (target host MHC) - can also occur in siblings as minor histocompatibility can also be targeted
- characterised by inflammation to different organs
- usually occurs when the recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells
- this reaction however may be beneficial → may prevent rejection and can be used as for treatment of cancer - graft-versus-TUMOUR effect
Pathological mechanism of graft rejection
Passenger leukocyte
method aka the direct method
o Before naïve alloreactive T cells can cause rejection they must be activated by APCs
that both bear the allogenic molecules and have costimulatory activity.
o Organ grafts carry with them antigen presenting cells of donor origin known as passenger leukocytes which act as a potent alloreactive stimulus.
o This route of sensitisation involves donor antigen presenting cell leaving the graft
and migrating to the regional lymph nodes.
o Here they can activate host T cells which bear the corresponding TCRs and thus initiate a CTL response.
The indirect method:
oClassic response to foreign proteins; uptake by
host APCs, processing and presentation via MHC class II.
o Activation of
macrophages causing
tissue injury and fibrosis and a B cell alloantibody
response
Describe iatrogenic immunosuppression
As a complication of the use of cytotoxic drugs or irradiation in tumour
therapy - neutropenic sepsis
Side effects of immunosuppressants
- nephro- and hepatotoxicity
- non specific and so inhibit the pro-inflammatory and regulatory immune effectors - this means that there is increased risk of oppertunistic infection amongst other diseases
Which pathway of allograft rejection happens in acute rejection?
direct pathway of allograft recognition where dendritic cells migrate from tissue graft to the recipient secondary lymphoid nodes and activate donor specific recipient T cells as alloreactie T cells bind to foreign donor MHC molecules. This then causes the production of CD8+ cytotoxic T cells that attack the graft, as well as Th1 cells that can activate macrophages that cause inflammation of the graft. The ignition of this immune response typically takes around a week, the graft being totally rejected after 12-14 days
Which pathway of allograft rejection happens in chronic rejection?
indirect pathway of allorecognition, apoptotic fragments of fonor cells phagocytosed by recipient dendritic cells, these contain donor antigens including MHC molecules, subsequently broken down and expressed on surface of dendritic cells with recipient MHC 2.
These are then bound by complementary CD4+ receptors on recipient T cells, resulting in the activation of the T cells which go on to provide help for naive B cells that are specific for the HLA allotypes of the graft (as well as B cells complementary for other donor antigens), resulting in the production of anti-graft antibodies.
These anti-graft antibodies can cause complement activation and will eventually result in loss of the tissue graft.
The rejection seen here is characterised by vascular changes in the graft that cause a stiffening and thickening of the vessel wall, decreasing the lumen size and gradually restricting the blood flow to the organ, eventually resulting in ischemia and loss of the grafts function.
In which part of the body is not HLA matching or immunosuppressive therapy needed following transplant?
Cornea transplants
