Autoimmune Flashcards
What causes APECED geneticaly?
Its a defect in hte AIRE gene, leading to a lack of expression of self antigens in thymic medullary epithelial cells
What is the clinical syndrome associate with APECED?
autoimmune and parathyroid disease
also see hypothyroidism, hypogonadism, vitiligo, pernicious anemia
also associatd with fungal infections due to targeting of IL 17
What is the genetic cause of autoimmune lymphoproliferative syndrome? (ALPS)
mutationi n Fas or Fas ligand
increased percentage of CD4/CD8 negative T cells
What is the clinical syndrome associated with ALPS?
high IgG, IgA, IgM; widespread lymphadenopathy, splenomegaly and autoimmune ctopenias
What is the disease associated with hypergammaglobulinemia, low insulin, low albumin, high IgE, skin test positive to all food, diffuse eczematous rash, cachexia, pallor, failure to thrive?
IPEX due to deletion of Foxp3 and loss of T reg cells
What are the strongest links to autoimmunity geneticaly?
MHC/ HLA genes
WHat are the 4 types of hypersensitivity reactions?
type 1: Immediate sensitivity (IgE mediated)
type 2: antibody mediated
Type 3: Immune complex
Type 4: delayed type hypersensitivity (T cells)
What disease is a type 2 hypersensitivity reaction associated with streptococcus infection?
Acute rheumatic fever
What are the 5 major manifestations of acute rheumatic fever?
J<3NES Criteria Joint (polyarthritis) Heart (cardtitis) nodules erythema marginatum sydenhams chorea
Diagnosis is 2 major or 1 major and 2 minor symptoms along with exclusion of other dxs
What is the tx of rheumatic fever?
penicillin prophylaxis until adulthood or lifelong dependent on severity
What are the treatments of antibody mediated diseases?
High does IVIG – controversial mechanism of action
Corticosteroids–prednisone short term
rituximab (anti-B cell therapy but not plasma cells)
Life threatening plasmapheresis
What are type 3 hypersensitvitiy reactions?
When antigens/antibodies comine in circulation; lead to activate complement with failure to clear and deposits in vasculature
What are the symproms of systemic lupus erythematosus?
malar rash
discoid rash
photosensitivity
oral/nasal ulcers
arthritis
serositis
cerebritis
nephritis
Labs:
ANA
Immune -dsDNA or Anti-SM
Autimmune cytopenias ITP AIHA
Need 4/11 for dx
Complement defects lead to early onset of what disease?
systemic lupus
What are type 4 hypersensitivity diseases?
delayed onset; cell mediated diseases by T cell either CD8 or CD4
What is the pathology associated with Rheumatoid Arthriitis?
pannus formation and aggregation of mononuclear cells
What are teh treatments for Rheumatoid Arthritis?
NSAIDS Antimetabolites that inhibit DNA synthesis --> methotrexate: folic acid analog --> azathioprine: purine analogue glucocorticoids (short term) monoclonal Ab to immune molecules anti-TNF anti-IL1 Anti-IL6
What are the Sx of dermatomyositis?
heliotropic rash ((sun sensitive), occurs on eyelids and bridge of nose, marked with edema soometimes) gottrons papules; (plaques on joints scaly) proximal muscle weakness capillary changes
What is the pathology behind dermatomyositis?
perifascicular atrophy
perivascular inflammatory infiltrate with CD4+ cells and B cells and Mphage
Necrosis of msucle occurs in periphery or wedge shape
What causes the vascular damage in dermatomyositis?
MAC complexes on vasculature
What are secondary causes of immunodeficiencies?
immunosuppressants malnutrition infections malignancies metabolic loss of lymphocytes or antibodies coolagen vascular disease
What can you see in neutrophil defects?
onset early in infancy severe bacterial infections abscesses gingival disease poor wound healing lack of pus common pathogesn -- catalase + organsims ie chronic granulomatous diease congenital neutropenia leukocyte adhesion deficiency
Initial test that all shoudl get with neutrophil defect?
CBC with differential (calculate ANC) oxidative burst (DHR)
complement defects cause what type of disease?
early age
early (C2, C4) defects
sinopulmonary infections, autoimmune disease
Late (c5-C9) defects
increase susceptibility to Neisserial infections
C3 defects, sever pyogenic infections
Complement defect work up includes what?
CH50
If 0 suspect complement deficiency
if low but not 0 assume complement consumption
B-cell antibody defects?
antibody deficiencies most common PIDs
Agammaglobulinemias usually present in first year or two of live; CVID at any age
Recurrent sinopulmonary bacterial infections
–mycoplasma and encapsulated organisms
enteroviral meningitis
chronic GI infections
ie XLA, CVID
B-cell/antibody defects work up?
CBC with DIF Quantitative immunoglobulins vaccine titers consider -CH50 -sweat chloride -CT sinuses/chest
T cell or combined T cell/ Bcell defects?
SCID-first year of life recurrent severe infections viruses fungi bacteria opportunistic
combined: SCID
T cell: 22q112DS di George
T cell/combined defect-work up
lymphocyte subset enumeration (flow cytometry)
cannot diagnose T cell deficiency by an ALC (all lymphocyte count) alone
Immunoglobulins
T cell proliferation (mitogens)
What is the genetic cause of X-linked scid?
mutation in common gamma chain of IL2 receptor and a bunch of other IL chains leading to lack of proliferation of T cells
Diagnositic SCID?
screening test for CBC of lymphocytepenia
confirmation of SCID done by flow cytometry and cell enumeration
What is screening test for SCID now in newborns?
T cell receptor excision circles
non replicating circular pieces of DNA in naive T cells generatied in process of making a t cell receptor
number of TRECs in SCID from qt-PCR will be low
22q11.2 microdeletion causes what?
diGeorge syndrome
What gene underlies many of the abnormalities of diGeorge syndrome?
TBX1
What is the clinical spectrum of 22q11.2 (diGeorge)?
CATCH22 cardiac defects abnormal fascies thymic hypoplasia cleft palate hypocalcemia 22nd chromosome many cases undiagnosed until late childhood Dx DNA microarray (preferred), FISH
What is X-linked aggamaglobulinemia?
Most common cause of aggammaglobulinemia. 1:100,000
screen for antibodies
Mutation in Btk (brutons tyrosine kinase) results in failure of differentiation of B cells
What is common variable immunodeficieency?
most common PIDD
onset at any age
What disesases are most common in CVID?
pulomary disease bronchiectasi and interstitial lung disease
cause of death is pulomnary disease or B cell lymphoma
GI problems also common
CVID -diagnosis how?
decrease in IgG and a low IgA or IgM
What is IgA deficiency?
most common Ab deficiency? (1:400) live births
vast majority subjects are normal with no phenotype
Why is IgA deficiency unique?
They can make heterophile antibodies, alsoc describe in EBV infection; can identify antigens that wasn’t originally made for
makes a lot of false positive results and false negatives because of heterophiles
Specific antibody deficiency?
Normal everything, but abnormal specific antibody response to immunization esp polysaccharide antigens
rarely need replacement Ab
What do both XLA and CVID have in common with exposure to vaccines?
low antibody response to vaccines
Dx studies in pts with Ab deficiency what do you do differently?
don’t use serological assays
look for antigens or use PCR exams
What is chronic granulomatous disease cause?
all forms functional absence of respiratory burst
X-linked is the most common cause
CGD clinical findings?
onset by age 2 pneumonia adenopathy hepatic abscess without obvious source sepsis osteomyelitis infection with catalse + bacteria
Diagnoising CGD test?
dihydrorhodamine (DHR preferred)
activate neutrophils, when exposed to DHR and measure if oxidative burst occurs becuase that would cause DHR fluoresence when oxidative
What is the definitive treatment for CGD?
bone marrow transplant
What is leukocyte adhesion deficiency?
lack of adhesion molecules most common LAD1 is a lack of tight adhesion
leads to lack of neutrophils because unable to leave bloodstream
What is the way to diagnose leukocyte adhesion deficiency?
flow cytometry
What is the typical infection of late complement deficiency?
increased susceptibility to neisseria
Early complement disease deficiency is usually associated with what?
autoimmune diseases including early onset Lupus
