Immunodeficency and Autoimmune Disorders Flashcards
Digeorge Syndrome
22q11 microdeletion leads to failure to develop 3rd and 4th pharyngeal pouch so dont get THYMUS (t-cell deficiency), parathyroids (hypocalcemia), and also get abnormalities of heart, great vessels and face.
No t-cells so cant fight viral and fungal infections
Sever Combined Immunodeficiency Syndrome (SCID)
Defective cell mediated (T-Cell) and humoral (b-Cell) immunity
Etiologies include
1) Cytokine Receptor defect = cytokines typically needed for proliferation and maturation of B-Cells and T-Cells
2) Adensoine Deamine Defficency = ADA deamnites adenosine and deoxyadenosine. Without these molecules build up and are toxic to lymphocytes
3) MHC class II deficiency = MHC II is necessary for CD4+ helper T-Cell activation and cytokine production
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation
Cytokine Receptor defect
SCID = cytokines typically needed for proliferation and maturation of B-Cells and T-Cells
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation
Adensoine Deamine Defficency
SCID = = ADA deamnites adenosine and deoxyadenosine. Without these molecules build up and are toxic to lymphocytes
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation
MHC class II deficiency
SCID = = MHC II is necessary for CD4+ helper T-Cell activation and cytokine production
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation
X-Linked Agammaglobulinemia
lack of Ig due to disordered B-Cell maturation as a result of mutated Bruton Tyrosine kinase (X-linked)
Presents after 6 months of life with recurrent bacterial, enterovirus (polio and coxi), and Giradia lamblia infections but mothers Ig protective for 1st 6 months.
Avoid live vaccines (polio)
Common Variable Immunodeficiency
Low Ig due to B-Cell or helper T-Cell defects
increased risk for bacterial, enterovirus (polio and coxi), and Giradia lamblia infections, as well as autoimmune disease and lymphoma
IgA Deficiency
Low serum and mucosal IgA MOST COMMON Ig deficiency Increaed risk for mucosal infection, especially viral Usually asymptomatic Can also see Celiac disease with low IgA
Hyper IgM Syndrome
Elevated IgM due to mutated CD40L of helper T-Cell or CD40 receptor of B-Cells. Without CD40 cant make or bind IL4 and IL5 which are cytokines necessary for Ig calss switching. Therefore get high IgM and low IgA,G,E
Get pyrogenic infections due to poor opsonization, especailly at MUCOSAL sites
Wiskott-Aldrich Syndrome
triad of thrombocytopenia, eczema, and reccurent infections ( deffective humoral and cellular immunity)
bleeding is major cause of death
Due to mutation is WASP gene = x linked
C5-9 Deficiencies
Increased risk for Neisseria infection (N gonorrhea and meningitidis
C1 inhibitor deficiency
get overactivation of complement that leads to increased vasodilation and vasuclar permeability. Get hereditary angioedema (edema of skin (PERIORBITAL) and mucosal surfaces)
Progression of T cell development and central tolerance
stem cells in bone marrow, then travel to thymus as double positive, if pass positive selection (can bind to MHC II) then become single positive, single positive undergo negative selection (don’t bind self antigen presented by dendritic cells and medullary epithelial cells, occurs in medulla of thymus), then exit as naive mature T-Cells
Autimmune Polyendocrine Syndrome
Medullary epithelial need AIRE to express self antigens. If missing then don’t express self antigen and get a failure in negative selection and T-Cells that are self reactive. As a result get Autimmune Polyendocrine Syndrome characterized by
1) hypoparathyroidism
2) Adrenal failure
3) repeated candida infections of skin and mucosa
Progression of B cell Development
Stem cells in bone marrow become immature Ig then undergo negative selection where RAGs edit light chains to try and make succesful light chain, if fail then then they die, if pass they exit as naive mature B cells
Peripheral Tolerance
1st signal is typically TCR of CD4 recognizes MHCII of dendrite. Then need dendrite to express B7 and interact with CD28 of T cell. this is the second signal. If no 2nd signal get anergy. If binds MHCII with self antigen chronically then T-Cell undergoes apoptosis by expressing FAS ligand that interacts with CD95?FAS receptor on same T-cell which leads to cell death. FASL can also bind other CD4 T-Cells’ CD95 and cause them to die
Autimmune Lymphoproliferative Syndrome
mutations in FAS apoptosis pathway. Lose FASL or FASR/CD95 or caspase 10 so T-cells dont die and make IgG against cells in blood leading to anemia or thrombocytopenia and get proliferation of self reactive lymphocytes and get lymphadenopathy and hepatosplenomegally. Can eventually progress to lymphoma
Regulatory T-Cells
CD4+ and suppress immune responses by expressing CTL4 that binds B7 to decrease 2nd signal
Also secrete IL10 which inhibits dendritic cells production of B7
Also secrete TGFbeta to inhibit activation of macrophages
Are CD4+, CD25+, and FOXP3 (needed for development and maintenance
Systemic Lupus Erythematous Sunlight Theory
Sunlight hits keratinocytes and causes them to apoptose. DNA is released and self reactive B lymphocyte sees nuclear material and makes Ab against it nuclear antigens.
Next time get UV damage, nuclear material is released, AB binds Ag at low levels, dendritic cells take up ABAg complexes and can activate denritic cell’s TLR and amplify the immune response by further activating B cells to make more Ab, so get increased AbAg complexes with subsequent UV damage.
Supported by high SLE incidence in Complement deficiencies (C1q, C4, and especially C2)
Classic Findings of SLE
In general it is a Type III hypersensitivity rxn (AgAb complexes)
- Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon
- Malar ‘butterfly’ rash or discoid rash, especially upon exposure to sunlight
- Oral or nasopharyngeal ulcers (usually painless)
- Arthritis (usually involving >2 joints)
- Serositis (pleuritis and pericarditis)
- Psychosis or seizures
- Renal damage
i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury.
ii. Other patterns of injury (e.g.,membranous glomerulonephritis) also occur. - Anemia, thrombocytopenia, or leukopenia (type II HSR)
- Libman‐Sacks endocarditis (small sterile deposits on BOTH side of the mitral valve)
- Antinuclear antibody (ANA; sensitive, but not specific)
- Anti‐dsDNA or anti‐Sm antibodies (highly specific)
Drug Induced SLE
Antihistone antibody is noted.
Caused by Hydralazine, procainamide, and isoniazid
Rarely involves kindey or CNS and resolves with removal of drug
Antiphospholipid Antibody Syndrome
associated with SLE in 30% of cases. Get antibody to proteins bound to phospholipids.
Anticardiolipin leads to false postive for syphilis tests
Lupus Anticoagulant leads to falsely elevated PTT (which is especially false cus they are actually hypercoaguable)
Can get arterial and venous thrombosis (DVT, hepatic vein thrombosis, and palcental thrombosis (multiple misscariages!!!)
Person needs to be on anticoagulants for life
Major complications of SLE
Death by renal failure or infection.
Also get accelerated Coronary Atherosclerosis
Sjogren Syndrome
Autimmune destruction of lacrimal and salivary glands.
Lymphocyte mediated damage (type IV hypersensitivity) with fribrosis)
Classically presents as dry eyes, dry mouth (xerostomia) and recurrent dental carries in an older woman
“cant chew a cracker and have dirt in eye”
ANA and anti-ribonucleoprotein (anti-SS-A/Ro and Anti SS-B/La)
anti SSA can cross placenta and cause neonatal lupus and congenital heart block
Often assoicated with other autoimmune disorders such as rheumatoid arthritis (see rheumatoid factor)
At increased risk for B-Cell (marginal zone) lymphoma which presents as enlargement of parotid gland
Scleroderma/Systemic Sclerosis
Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis)
Localized Scleroderma
Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis) that only involves the skin.
Highly associated with Antibodies against DNA topoisomerase II
Systemic Sclerosis
Limited vs diffuse
Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis) that involves both skin and visceral organs
Limited = limited involvement of skin (mostly HANDS, face and neck) with late visceral involvement.
CREST Syndrome = Calcinosis/anti-Centromere Antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (wrinkles of hand disappear), Telangiectasias of skin
Diffuse = involves skin and any visceral organ (especially GI, but also vessels, lungs, heart, and kidneys. Usually have DNA topoisomerase I antibodies
Mixed Connective Tissue Disease
Autoimmune mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis (inflmation of joints nad muscles)
See serum antibodies against U1 ribonucleoprotein.
