ICL 6.1: Autoimmunity Flashcards
what is the significance of immunological tolerance?
all individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
therapeutic potential: inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy
what is the pathology behind autoimmunity?
- susceptibility genes –> failure of self-tolerance –> persistence of functional self-reactive lymphocytes –> activation of self-reactive lymphocytes –> immune responses against self tissues
- environmental triggers like infections or tissue injury –> activation of self-reactive lymphocytes –> immune responses against self tissues
what environmental factors can induce autoimmune diseases?
- virus clustering (RA, Sjögren’s s., SLE, MS)
- infectious microorganisms (molecular mimicry)
- sun exposure (SLE)
- exogenous estrogens, sex hormones in general
- obesity
which gender is more prone to autoimmune diseases?
women are WAY more prone to like every single autoimmune disease
however, this doesn’t eliminate the possibility that a male will have an autoimmune disease!
what are the characteristics of autoimmunity?
- existence of self antibodies
- it is potentially reversible!!
- higher incidence in older people
why is autoimmunity higher in older populations?
when a cell dies, it releases the contents of the nucleus which can stimulate the immune system to produce antibodies
so everybody has a small amount of auto-antibodies in their body
as you get older, more neutrophils and cells die and you generate more auto-antibodies
autoimmunity is not a problem, it’s a normal process!
what are the characteristics of autoimmune disease?
there is severe 1. tissue damage!***
- there are clinical symptoms associated with the tissue damage
- protracted course but usually fatal
- familial clustering
what are the two categories of autoimmune diseases?
- organ specific
2. non-organ specific
what are the characteristics of organ-specific autoimmune diseases?
- autoimmune attack vs. self-antigens of given organ
- it results in a damage of organ structure and function
- treatment is focused on the replacement of organ function
what are the characteristics of non organ-specific autoimmune diseases?
- widespread self-antigens are targets for autoimmune attack
- damage affects such structures as blood vessels, cell nuclei etc.
- treatment is aimed to inhibit activation of the immune system
which diseases are examples of organ-specific autoimmune disease?
- type I diabetes
- goodpasture’s syndrome
- multiple sclerosis
- grave’s disease
- Hashimoto’s thyroiditis
what are examples of non organ-specific disease?
- rheumatoid arthritis
- scleroderma
- SLE
- primary Sjogren syndrome
what kind of autoimmune disease is SLE?
non organ specific
it effects your skin, heart, kidney, joints; it’s systemic!
what mediates autoimmune diseases?
autoimmune diseases caused by IgG mediated mechanisms require T cell help in order to produce antibodies
since IgG is involved, hypersensitivity reactions II, III and IV are involved
transfer of T cells from an animal with autoimmune disease to a healthy animal can transfer disease!!
autoimmune diseases are often linked to what?
specific MHC genes
MHC genes regulate T cells!
when do autoimmune diseases happen?
when auto-reactive T cells or auto-antibodies cause tissue damage through hypersensitivity reaction types II, III and IV
what is a type II hypersensitivity reaction?
IgG and IgM antibodies bind to antigens on human cells/tissue
this leads to lysis by complement or phagocytosis
which autoimmune diseases are type II hypersensitivity reactions?
- autoimmune hemolytic anemia
- autoimmune thrombocytopenia purpura
- goodpasture’s syndrome
- pemphigus vulgaris
- acute rheumatic fever
- grave’s disease
- myasthenia gravis
- insulin-resistant diabetes
- hypoglycemia
how are type II hypersensitivity reactions related to autoimmune disease?
antibodies that cause disease are most often autoantibodies against self antigen of human cells or tissues
Ab may modify the function of cells by binding onto receptors that cause disease by stimulating or blocking receptor function
human cells = autoimmune hemolytic anemia
tissues = good pasture’s syndrome, acute rheumatic fever
what can cause autoimmune hemolytic anemia?
after administration of certain drugs (like penicillin)
drug molecules bind to surface components of human cells and create new epitopes to which the immune system is not tolerant
these epitopes stimulate the formation of IgM and IgG antibodies that are specific for the conjugate of drug and cell surface component
what is type III hypersensitivity reaction?
antibodies may cause tissue injury and disease by forming
immune complexes that deposit in blood vessels or tissues
smaller immune complexes are less efficient at fixing complement, they tend to circulate in the blood and become deposited in blood vessel walls
when these complexes accumulate at such sites, they become capable of fixing complement and initiating tissue-damaging inflammatory reactions
Ag-Ab complexes activate complement
what type of hypersensitivity reaction is SLE?
type III
SLE is mediated by antibodies against DNA and other nuclear components
what lab results would be diagnostic of SLE?
immunoflurescence shows her blood contains an anti-nuclear antibody
skin biopsy shows to contain IgG and complement deposits
which parts of the body are commonly effected in immune complex disease?
joint, skin and kidney involvement are very typical of immune complex disease
what is type IV hypersensitivity reactions?
they are caused by T cells (CD4) specific for the sensitizing antigen, that release cytokines which leads to macrophage activation
type IV hypersensitivity reactions may also include killing of sensitized targets by cytotoxic T cells (CD8)
which autoimmune diseases are classified as type IV hypersensitivity reactions?
- insulin-dependent diabetes mellitus
- rheumatoid arthritis
- multiple sclerosis
- Celiac disease
what is insulin-dependent diabetes mellitus?
it’s a type IV hypersensitivity reaction
there is an auto-antigen against pancreatic β-cell antigen
this leads to β-cell destruction
what is rheumatoid arthritis?
there is an auto-antigen against an unknown synovial joint antigen
leads to joint inflammation and destruction
what is multiple sclerosis?
auto antigen against myelin basic protein, proteolipid protein
leads to brain degeneration and paralysis
what is Celiac disease?
auto antigen against gluten modified by tissue transglutaminase
leads to malabsorption of nutrients and atrophy of intestinal villi
what isn’t being produced when someone has insulin-dependent diabetes mellitus? why?
the islets of Langerhans contain several cell types secreting distinct hormones; each cell expresses different tissue-specific proteins
β cells secrete insulin
in insulin-dependent diabetes an effector T cell recognizes peptides from a β cell-specific protein and kills the β cell
someone officially has type I diabetes once there are insufficient b cells to provide the insulin necessary to control the level of glucose in the blood
glucagon and somatostatin are still produced by the α and δ cells but insulin can’t eb made without the β cells
what would a tissue biopsy of someone with insulin-dependent diabetes mellitus?
brown!!
the brown is from the destruction of insulin secreting β cells of the pancreas
what’s the difference between insulin dependent and insulin independent diabetes?
T cells kill the pancreas β cell so not enough insulin is not produced = type I diabetes
insulin independent diabetes is when you have enough insulin released but the problem is that there’s an antibody that recognizes the insulin receptor and destroys it = type II diabetes
what do the α, β and δ cells of the pancreas make?
α = glucagon
β = insulin
δ = somatostatin
what are the characteristics of type I diabetes?
type I diabetes is characterized by loss of the insulin-producing beta cells of the pancreas
the majority of typeI diabetes is of the immune-mediated nature, in which beta cell loss is a T-cell-mediated autoimmune attack
**low level of serum insulin is indicative of type I diabetes
what are the characteristics of type II diabetes?
typeII diabetes mellitus is characterized by insulin resistance
the defective responsiveness of body tissues to insulin is believed to involve the antibodies against insulin receptor that reduce insulin sensitivity = type II hypersensitivity reaction
**serum insulin levels are normal/high because it’s a problem with the insulin receptor, not insulin itself
the most dangerous complications of obesity are type II diabetes and vessel disease
is IDDM effected by genetics?
yup. if an identical twin develops IDDM, there is a 35% chance his or her twin will also do so
IDDM often occurs in people who inherit the HLA alleles DQ2
which gene is related to IDDM?
DQ2 HLA alleles
in most HLA-DQ alleles, position 57 in the HLA-DQ β chain is occupied by an aspartic acid residue
with HLA-DQ2, this position is replaced by another amino acid residue, and this change has reduced binding for a pancreatic islet cell antigen
autoreactive T cells cannot be deleted in the thymus and the potential for autoimmunity to increased
what is Hashimoto’s disease?
the thyroid loses the capacity to make thyroid hormone
Hashimoto’s disease seems to involve a CD4 T cell response, and both T cells and antibodies specific for thyroid antigens are produced
lymphocytes infiltrate the thyroid, causing a progressive destruction of the normal thyroid tissue
patients with Hashimoto’s disease become hypothyroid, and eventually are unable to make thyroid hormone
what is the treatment for Hashimoto’s disease?
replacement therapy with thyroid hormone
