Lecture 3- immunodeficiency and autoimmunity Flashcards
what are the general principles of the immune system?
-multi-layer defense
-network of pathogen recognition
effective inter-cellular communication
-many mechanisms for pathogen clearance
-adaptive response to changing pathogens
-self-regulation
-limitation of host damage
self-regulation of immune system
important in terms of causing disease. when self-regulation is not correct, disease results
innate immune system
neutrophils, macrophages produce simple chemicals that kill bacteria
adaptive immune system
more precise and potent but this needs regulation
what are PRR?
pattern recognition receptor. they recognise components of the microorganism
what are the different barrier components of the immune system
SKIN
tears
saliver
name the different mechanisms of the immune system
- barrier and chemical mechanism
- PRR
- cellular-such as phagocytes/natural killer cells
- humoral
- cellular
where are the cells of immune system produced?
bone marrow from precursors
which precursors do innate immune cells come from
myeloid precursors
where do dendritic cells, macrophages, and neutrophils arise from?
common stem cell
what do lymphoid precursors divide into?
B and T cells
where do B cells mature?
initially mature in the bone marrow
where do T cells mature?
mature in the thymus.
when released into the periphery, it matures further into specialised TH1 and TH2 cells
autoimmune disease
range of conditions where own immune system attacks target or systemic autoimmunity.
has distinct clinical entities
breakdown of self-tolerance
environmental factors acting on favourable genetic background
requirements for autoimmune disease to develop
genetic predisposition
environment
immune regulation
what is HLA
human leukocyte antigen
where are HLA molecules found?
found at the surface of antigen presenting cells and can attach to variety of proteins
what causes rheumatoid arthritis?
shared epitopes, several HLA alleles that can present certain proteins in ways to cause the disease.
these are proteins that can be citronated and cause disease chain reaction
what are the risk factors of rheumatoid arthritis?
smoking –> cause citronisation more rapidly, leading to damaged proteins and initiate autoimmune response
what is HLA-DRB1?
The HLA-DRB1 gene provides instructions for making a protein that plays a critical role in the immune system. The HLA-DRB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex.
The protein produced from the HLA-DRB1 gene, called the beta chain, attaches (binds) to another protein called the alpha chain, which is produced from the HLA-DRA gene. Together, they form a functional protein complex called the HLA-DR antigen-binding heterodimer. This complex displays foreign peptides to the immune system to trigger the body’s immune response
which HLA-DRB1 is associated with tye 1 diabetes?
DR3,DR4
which HLA-DRB1 is associated with graves disease?
DR3
which HLA-DRB1 is associated with multiple sclerosis?
DR2
which HLA-DRB1 is associated with systemic lupus erythematosus (SLE)?
DR2,DR3
Rheumatoid arthritis
DR1, DR4
which genetic defect is linked with autoimmune polyendocrine sydrome type 1?
AIRE
what is the mode of inheritance for autoimmune polyendocrine syndrome type 1?
Autosomal recessive
what is the mechanism of disease for autoimmune polyendocrine syndrome type 1?
adaptive immunity affected
defective thymic expression of self antigen
which genetic defect is linked with immune dysregulation, polyendocrinopathy, enteropathy
FOXP3
which genetic defect is linked with type 1 diabetes?
insulin gene
which genetic defect is linked with type 1 diabetes, rheumatoid arthritis, autoimmune thyroid disease?
PTPN22
which genetic defect is linked with type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis
CTLA4
which genetic defect is linked with SLE, type 1 diabetes, rheumatoid arthritis?
PD1
which genetic defect is linked with autoimmune polyendocrine syndrome type 2?
unknown
which genetic defect is linked with SLE?
IRF5
complement deficiencies C1Q, C2, C4
what is the mode of inheritance for diseases caused by FOXP3 gene?
X-linked recessive
what is the mechanism of disease for diseases caused by FOXP3 gene?
- adaptive immunity affected
- defective production of regulatory T cells
what is the mechanism of disease for type 1 diabetes caused by deficiency in insulin gene?
- adaptive immunity affected
- reduced thymic expression of insulin
- reduced negative selection of T cells
what is the mechanism of disease for diseases caused by deficiency in PTPN22 gene?
- adaptive immunity affected
- reduced thymocyte responsiveness to negative selection
- reduced regulatory T cell function
what is the mechanism of disease for diseases caused by deficiency in CTLA4?
- adaptive immunity affected
- reduced regulatory T cell function
- inadequade negative signalling in effector T cells
what is the mechanism of disease for diseases caused by deficiency in PD1?
- adaptive immunity affected
- inadequate negative signalling in effector T cells
what is the mechanism of disease for autoimmune polyendocrine syndrome type 2
- adaptive and innate immunity affected
- reduced regulatory T cells function
what is the mechanism of disease for SLE caused by deficiency in IRF5 gene?
- innate immunity affected
- altered signalling thresholds in TLR(toll-like-receptor) pathway
what is the mechanism of disease for SLE caused by deficiency in complement C1Q, C2, C4?
- adaptive and innate immunity affected
- altered pathogen recognition
- altered effector functions (immune complex clearance)
what happens if the thymus doesnt have AIR gene?
it cannot remove potentially self-reactive T cells
what are FOXP3 genes important in?
development of T regulatory cells, which is produced centrally in thymus
what are other causative associations of autoimmune disease?
- sex –> hormonal influence. woman»_space; men
- age –> more common in elderly
- environmental triggers –> infection, trauma-tissue damage, smoking
autoreactive B cells and autoantibodies are…
- directly cytotoxic
- activation of complement
- interfere with normal physiological function
autoreactive T cells are…
- directly cytotoxic
- inflammatory cytokine production
what is organ specific autoimmune disease?
- affect a single organ
- autoimmunity restricted to autoantigens if that organ
- overlap with other organ specific diseases
- autoimmune thyroid diseases is typical
what is systemic autoimmune diseases?
- affect several organs simultaneously
- autoimmunity associated with autoantigens found in most cells body
- overlap with other non-organ specific diseases
- connective tissue diseases are typical
what is hashimotos thyroiditis?
- destruction of thyroid follicles by autoimmune process
- associated with auto-antibodies to thyroglobulin and thyriod peroxidase
- leads to hypothyrodism
what is Grave’s disease?
inappropriate stimulation of thyroid gland by anti-TSH-auto-antibody
-leads to hyperthyrodism
list connective tissue autoimmune diseases
- SLE
- scleroderma
- polymyositis
- sjogrens syndrome
name a non-specific diagnostic test used for auto-immune disease
inflammatory markers
name a disease specific diagnostic test used for auto-immune disease
- auto-antibody testing
- HLA typing
why measure autoantibdies
- diagnostic
- early diagnosis
- pathogenic
- subtyping of patients
- mointoring of exacerbation/remission
- exclusion of diagnosis
- cost of treatment
what is immunosupression?
a natural or artificial process which turns off the immune respnse, partially or fully, accidentally or on purpose
-can result in immunodeficiency
what is immunodeficiency?
the lack of an efficient immune system-susceptibility to infections
what are the causes of immunodeficiency?
- infection –> the result of transient immunodeficiency
-secondary to effects of external factors
-primary immunodeficiency –> caused by genetic defects in individual components of immune system
-
what the causes of secondary or acquired immunodeficiencies?
- stress
- surgery/burns
- malnutrition
- cancer –> esp. lymphoproliferative disease
- immunosupressive effect of drugs inc. cancer therapy
- irradiation (clinical or other)
- AIDS
- other infection e.g. measles, TB
when are primary immunodeficiency often diagnosed?
childhood - recurrent infection often suggests immunological problem
what does SCID stand for?
severe combined immunodeficiency syndrome
what happens if there is a defect in both B and T cells?
- SCID
- combined immunodeficiency syndrome
- bone marrow transplantation curative
- gene therapy
what are symptoms of defects in T cells?
recurrent infection with opportunistic infection, bacteria, viruses, fungi (candida), protozoa (pneimocystis)
why are defects in T cells more severe than defects in just B cells?
because T cells are needed for normal functioning of B cells
