Please enable JavaScript.
Coggle requires JavaScript to display documents.
IMMUNOGENETICS
Involves two main aspects:
Production of apparently…
IMMUNOGENETICSInvolves two main aspects:
- Production of apparently infinite numbers of different, specific antibodies
- Ability to distinguish self from non-self and mount an immune response to almost any foreign cell or antigen (or altered self)
Autoimmune
Due to adaptive immune reponse mounted against self antigensCan be divided into 2 groups
- Organ specific
Diabetes, Hashimoto
- Systemic
Lupus, Sjorgen's
Familial clustering stays true to the groupAssociated with HLA types
Type 1 Diabetes
- Was called 'juvenile onset'
- Follows development of antibodies to pancreas
- Symptoms occur after more than 80% of the insulin-making cells are destroyed
- May be due to cross-reactivity after viral infection
Celiac Disease
- 1 in 100 people of european ancestry
- Due to immune response within the gut lining
- Associated with HLA-DQ2 type
- Requires exposure to gluten
- Symptoms include
- diarrhea
- abdominal pain
- weight loss
- anemia
- Can progress to malnutrition, iron deficiency
- Increased in Down syndrome, Turner syndrome, selective IgA deficiency and autoimmune disorders
Ankylosis Spondylitis
- chronic inflammatory arthritis of the spine
- typically appears in adolescents/early adults
- results in fusion of the vertebrae +/- joints
- acute iritis associated in up to 40%
- multigenic and multifactorial
- Associated wtih HLA-B27
- Worse in men
- 0.2% to 1% of europeans
Immunodeficiencies
- Caused by LOF of any part of the immune system
ACQUIREDEnvironmental
- (viruses) HIV/AIDS
- Malnutrition
- Induced (e.g., medication)
Multifactorial
- Common variable immunodeficiency (CVID)
INHERITED
B-cell
x-linked agammaglobulinemia
IgA deficiency
Hyper-IgM
T-cell
SCID
Other
Ataxia Telangiectasia
Wiscott-Aldrich syndrome
Phagocytosis Defects
Chronic granulomatous disease
Complement Defects
Hereditary angioneurotic edema
Job's Syndrome (AD-HIES)
Classic triad
- recurrent skin boils (pockets of infection; "cold")
- cyst-forming pneumonias
- extreme IgE elevations
- should be below 120
- in JS, significantly higher than this
Facial phenotype emerges in teens
broad nose
coarse facial features
high palate
deep set eyes
facial asymmetry
- retain their baby teeth
- osteopenia
- fractures with minimal trauma
- chronic yeast-like skin infections
STAT3 mutations
Rare
Treatment: Antibiotics
Other Immunodeficiency SyndromesDNA repair defects
- Nijmegen breakage
- Bloom syndrome
- ICF
- homozygous PMS2
- Riddle syndrome
Immune-osseus dysplasia
- cartilage hair hypoplasia
- Schimke syndrome
Hyper-IgE syndromes
Dyskeratosis Congenita
Comel-Netherton s.
VODI
IKAROS deficiency
IPEX syndrome
X-Linked Agammoglobulinemia
- aka Bruton's agammaglobulinemia
- occurs in 3 to 6 million males, panethnic
- Mutations in Btk
- Blocks B cell development
- they recognize the antigen
- cannot produce the antibody
- Recurrent, severe or unusual infections in first 2 years of life
- Treated by regular infusions of IVIG
- intravenous immunoglobulin
- basically a shot of antibodies
Wiskott-Aldrich syndrome
- X-linked disorder
- Textbook triad
- Low platelet counts (easy bruising, easy bleeding)
- Eczema (80%)
- Recurrent infections (esp. ear)
- 1 to 4 per million males, panethnic
- rare
- WAS mutations
- can develop autoimmunity
- against blood cells; hemolytic anemia; similar to SCD
- destroy their own platelets
- individuals exposed to MONO may develop lymphoma (13%)
- Treatment: transplant
Ataxia Telangiectasia
- Autosomal recessive
- will develop either bone marrow failure or lymphoma/leukemia (up to 38%)
- 60-80% will have immunodeficiency
- can present with low IgA
- 1 in 40000 to 100000 births in USA
- symptoms appear between 1-4 yrs
- ataxia appears around age 2
- Oculocutaneous telangiecstasia by age 6
- recurrent infections
- ATM mutations
- Treatment: antioxidants, IVIG
Selective IgA Deficiency
- *MOST COMMON IMMUNODEFICIENCY
- You don't make IgA
- Affects up to 1 in 500 people
- More common in males
- range from asymptomatic to recurrent infections
- many people don't know
- therefore, infections can be mild
- associated with autoimmune diseases
- moderately increases risk of GI cancer
- No specific treatment
Hyper-IgM
- Low serum IgG and IgA which leads to a lot of IgM
- T cells don't appropriately signal the B cells
- so you don't get that recombination and hypermutation in the B cells
- Recurrent infections, chronic diarrhea
- May be anemic and low platelets, PMNs
- Autoimmune disorders, liver disease
- May be X-Linked, recessive, or (rarely) dominant
- males have higher chance for lymphoma
- Can accompany ectodermal dysplasia (IKBKG)
- ~1 in 500000 males (XL)
- Treatment: IVIG, transplant
Chronic Granulomatous Disease
- disorder that occurs if the phagocytes don't work
- phagocytes surround antigen, but they can't destroy it
- 2/3 of cases are X-linked, the remainder are recessive
- 1 in 200000 in the USA
- Caused by inability to kill engulfed pathogens
- recurrent infections, atypical organisms
- arthritis, bone infections, blood infections
- Most diagnosed in childhood
- When x-linked, caused by CYBB mutations
- Treatment: Antibiotics/antifungals, interferon, transplant, gene therapy sometimes works, sometimes not
Severe Combined Immune Deficiency
- t cells are absent, or low, or nonfunctioning
- severe disorder, can be syndromic
- no dominant forms
- 1 in 50000 births
- Multiple genetic etiologies
- single gene (ADA deficiency)
- syndromic (22q, CHARGE)
- Uniformly fatal by year 1 if not treated
- Most do NOT have fmhx
- Transplant < 3 months has best outcome
- gene therapy trials on-going
- ALL have low or absent T cells
- MA offers NBS for SCID
- DNA testing, usually it's a protein assay
- How to detect SCID
- look for evidence of T cells
- uses marker of T cell development
- TRECs
- t-cell receptor excision circles
- which is a DNA product
Immune Diversity
- Recombination
- Somatic Mutation
- "Junctional" variation
- RNA editing
Recombination
- the genes for the variable region of the antibody are found in a row down a chromosome
- they have to splice together
- this splicing is not exact and produces variability
Somatic Mutation
- adds to diversity
- programmed process
- mutations are required in order to protect you
- without mutations, no variety
-
Antibody TypesIgM
- first to emerge
- many binding domains
- not very specific
- becomes more specific as time goes on and becomes...
IgG
IgA
- Found in mucosa, breastmilk
- tends to be specific, somewhere in between IgM and IgG for specificity
IgE
- active against parasites
- active against allergic responses
IgD
More info
- if a baby doesn't make antibodies
make sure they breast feed
- whatever the mom is exposed to, the baby is also exposed to
- recommended that mom's get the flu shot
Response time
- Our bodies take some time for B cells to mature and figure out what they're fighting and fight it off
- persist until sickness goes away and then your body stops making it
- when your body is exposed to it again, your antibodies come out within a day
- if your body hasn't seen it before, it has to do this process all over again
Overarching Concepts
- Immune system development is key to its function
- T and B cell maturation leads to immunity
Disease results from too little or too much
- SCID = LOF
- Reaction vs self = autoimmune disorders
ANATOMY
- lymph nodes
- skin
- tonsils
- cilia
- spleen
- thymus
- thymus is missing in 22q11.2 deletion disorder
- liver
- bone marrow
- blood
MECHANISMS
- Direct cell-cell interaction
- phagocytosis
- antigen-presenting cells
- Release of chemicals to induce reaction
- Complement
- Cytokines
- Antibodies
CELLS
- T & B cells
- Neutrophils aka PMNs
- Red blood cells
- others
Determination of Self
- development of tolerance
- selection occurs in thymus or lymph nodes
- Self-reactive lymphocytes are culled
-