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Flashcards in Autoimmune Diseases Deck (73):

What are the two factors that combined together lead to autoimmune disease?

inheritance of susceptibility genes and exposure to environmental triggers


What groups of genes contribute the most to autoimmune disorders?

HLA genes


How can infections lead to autoimmunity? 4 ways...

1. up-regulate the expression of co-stimulators on APCs meaning APCs that carry self antigens might still activate T cells that will them be reactive against self
2. Molecular mimicry - where antigens from the infection look like self antigen enough to have cross-reactivity
3. Some viruses can cause polyclonal B-cell activation, which may result in production of autoantibodies
4. infection leads to tissue injury which may release self antigens and structurally alter self antigen sot hey are able to activate T lymphocytes


Describe the typical clinical course of untreated autoimmune disease.

They tend to be progressive: there may be sporadic relapses and remissions, but overall ther is inexorable tissue damage if untreated


Why are systemic autoimmune diseases often reffered to as collagen vascular diseases?

they tend to involve blood vessels and connective tissue


What's the udnerlying pathologic mechanism of systemic lupus erythematosis?

it's a multisystem autoimmune disorder characterized by the formation of multiple autoantibodies, particularly antinuclear antibodies that results in widespread multi-organ tissue damage


What organ systems are most often affected by SLE?

skin, joints, kidney, serosal membranes


Why do people with lupus often have cytopenias?

because they often have antibodies directed against red cells, platelets and lymphocytes


Why do patients with SLE often have false positive syphilis tests and false prolongation of the PTT?

Because they often make anti-phospholipid antibodies that interfere with the reagents in these tests


Because of the anti-phopholipid antibodies, patients with SLE often have secondary anti=phospholipid antibody syndrome, which is associated with what?

venous and arterial thrombosis
spontaneous miscarriages
cerebral ischemia


What are some of the environmental triggers we think play a role in the onset of SLE?

infections, UV light, estrogen, extreme stress


What sort of hypersensitivity reaction leads to the majority of the tissue injury in SLE?

type 3 - the deposition of antigen-antibody complexes


What are the clinical signs/criteria for SLE? (SOAP BRAIN MD)

Oral ulcers
blood (hematologic disorders - cytopenias)
renal disorder
antinuclear antibody
immunological disorders (other autoantibodies)
neurologic disorders
malar rash
discoid rash


Why can SLE involve multiple organ systems?

Because it causes acute necrotizing vasculitis, which can happen anywhere - in any organ


Why do you get kidney issues in lupus?

you get immune complex deposition in the glomeruli


How does the joint involvement in lupus differ from that in RA?

it's non-erosive and non-deforming, involving small joints


What are the effects of lupus on the lungs?

pleuritis, pleural effusions, interstitial fibrosis


What's the most ocmmon cause of death in patients with lupus?

infection due to immunosuppression


What is the best screening test for SLE?

start with an ANA
then follow-up a positive ANA with anti-dsDNA and anti-smith antibodies


What's the underlying pathologic mechnanism of RA?

1. exposure to an arthritogenic antigen in predisposed individuals
2. initial acute arthritis leads to a continuing autoimmune reaction with activation of CD4+ help T cells and the release of inflammatory mediators and cytokines
3. you get a nonsuppurative proliferative and inflammatory synovitis that progression to destruciton of the articular cartilage and ankylosis of the joints


What two alleles are especially associated with risk for RA?



What type of protein formed in the body (especially in smokers) has been implicated as a potential autoantigen in RA?

citrullinated proteins
(proteins modified by enzymatic conversion of arginine to citrulline)


What's the term for the mass of inflamed synovium that grows over joint cartilage in affected joints for RA?



Besides the anti-cyclic cirtullinated peptide antibodies, what antibody is seen in RA? Is it more or less specific than the AACP?

rheumatoid factor (IgM autoantibodies to Fc portion of IgG)
It's less specific because it can be seen in 5% of healthy individuals


What is the underlying pathogenesis of Sjogren syndrome?

Pathogenesis is thought to be related to aberrant T and B cell activation - you get lymphocytic inflammation and fibrosis of lacrimal and slaivary glands and potentially parotid gland enlargement


What are the typical pathologic and clinical findings of sjogren's syndrome/

1. dry eyes (keratoconjuncitivtis sicca)
2. dry mouth (xerostomia)


What are the antibodies against in sjogren's syndrome?

SS-A and SS-B, but it's not specific


What type of neoplasm can be seen in sjogren syndrome?

increased risk for lymphoma (marginal zone lymphoma in aprticular)


What's the underlying pathogenesis of scleroderma (systemic sclerosis)?

cause unknown, but they think it's an abnormal immune response by CD4+ T cells to unknown antigens, with release of cytokines that activate inflammatory cells and fibroblasts

You get ischemic damage and fibrosis in affected organs


What antibody is often present in scleroderma?

antibodies to Scl-70, which is DNA topoisomerase 1
some also have anti-centromere antibodies


What are the two types of scleroderma?

1. diffuse scleroderma - widspread skin involvement at onset and rapid progression to visceral involvement
2. limited scleroderma - skin involvedment confined to fingers, forearms and face with late visceral involvement


Patients with the limit scleroderma type oftne develop what syndrome? With what symptoms?

CREST syndrome
raynaud's phenomenon
esophageal dysmotility


What's the most common cause of death in scleroderma?

interstiaial lung fibrosis leading to respiratory failure


What classic rash is associated with dermatomyositis?

violaceous discoloration of the upper eyelids associated with periorbital edema

also scaling erythematous eruption or dusky red patches over the knuckles, elbows and knees


What muscle involvement usually comes first in dermatomyositis?

muscle weakness in proximal muscles first - symmetric
often accompanied by myalgias


What is the pathogenesis of dermatomyositis thought to be?

immunlogic injury to small blood vessels and capillaries in the skeletal muscle, perhaps secondary to autoantibodies and activation of T lymphocytes


How do you treat dematomyositis?

immunosuppressive agents


What is the difference between polymyositis and dermatomyositis?

polymyositis has similar muscle and systemic involvement, but no skin involvement


What is the pathogenesis of polymyositis thought to be?

T cell-mediated injury of myocytes as well as autoantibodies called Jo1 antibodies (RNA synthetase)

you get lymphocytic inflammation invading muscle fibers (but no perifascicular atrophy seen in dermatomyositis)


What's secondary sjogren syndrome? Is it more or less common than primary sjogren's?

It's when you get sjogren associated with one of the six main systemic connective tissue diseases - seconary is more common than primary


Some patients present with an overlap of autoimmune diseases. What disease do they have an what antibody is likely present?

mixed connective tissue disease

U1-RNP antibody (against a ribonucleoprotein particle containing U1 ribonucleoprotein)


name the likely disease based on antibody: cyclic citrullinate peptide antibodies



name the likely disease based on antibody: ANA, ribosome P antibodies, dsDNA antibodies, anti-sm antibodies?



name the likely disease based on antibody: anti-centromere antibodies?

CREST syndrome with scleroderm


name the likely disease based on antibody:U1-RNP antibody?

mixed connective tissue disease


name the likely disease based on antibody: Jo1



name the likely disease based on antibody: anti-Scl 70 (topoisomerase 1)



name the likely disease based on antibody: SS-A or SS-B

sjogren syndrome


What malfunctions in X-linked agammaglobulinemia?

Burton tyrosine kinase isn't working, so you don't get appropriate B cell maturation


What happens in peripheral blood in x-linked agammaglobulinemia? lymph nodes?

almost no B cells
decreased or absent gammablobulins
no plasma cells
underdeveloped germinal centers
Note: T cell mediated reactions ar enormal


What's the inheritance pattern for x-linked agammaglobulinemia?

x-linked recessive, so mostly seen in males


What infections ar epatients with agammaglobulinemia susceptible to?

sinopulmonary bacterial infections
haemophilus influenza, streptococcus pneumonia, or staphylococcus aureus

also to certain viral infections like enteroviruses

persistent Giardia lambia due to lack of IgA in GI tract


What's the treatment of agammaglobulinemia?

administration of prophylactic immunoglobulin therapy


How does common variable immunodeficiency differ in terms of lab tets from agammaglobulinemia?

CVID patients have normal numbers of B cells in the peripheral blood, but these B cells don't mature into plasma cells, so they also have decreased gammaglobulins


CVID patients are susceptble to the same infections as those with agammaglobulinemia, with what additional viral infection?

herpes viruses


How does CVID differ from agammaglobulinemia in terms of epidemiology and age of onset?

agammaglobulinemia occurs mostly in males with onset around 6 months of age

CVID affects males and females equally and the age of onset is later - childhood or adolescence


What happens in isolated IgA deficiency?

B cells aren't able to different into IgA-producing plasma cells, so IgA levels are decreased


What infections are people with IgA deficiency susceptible to?

mucosal defenses are weak, so increased sinopulmonary infections and giardia

also high frequency of respiratory tract allergies and increased autoimmune disease - can have fatal anaphylactiv reacitons to blood products


What happens in hyper-IgM syndrome? Why?

patients can make IgM, but cna't class switch to make IgG, IgA or IgE

ths issue seems to stem from the Cd4+ T cells being unable to deliver activating signals to B cells and macrophages - either because they don't express CD40 ligand or because of defect in activation-induced deaminase enzyme


What infections are people with hyper-IgM syndrome sysceptible to?

pyogenic infections
pneumonia from pneumocytsitis jiroveci

also cytopenias


What happens in DiGeorge Syndrome?

Development failure of the 3rd and 4th pharyngeal pouches, so you don't get thymus or parathyroid glands

this means they have a variable loss of T-cell mediated immunity and tetany


Is DeGeorge usually familial or spontaneous? What's the mutation?

usually sporadic (90%)

it's a deleiton of a gene on chromosomes 22q11


What infections will DiGeorge patients be susceptible to?

fungal, viral and pneumonocystis jiroveci infections


What's the most common genetic defect in SCID? inheritance pattern?

x-linked recessive mutation in the gene encoding the common gamma-chain subunit of cytokine receptors

this means they have reduced cytokine signalling leading to T cell development impairment

(B cells are normal, but antibody synthesis imparied due to lack of Th cells)


What's the second most common genetic defect in SCID? inheritance pattern?

autosomal recessive deficiency of adenosine deaminase, so you get an accumulation of deoxyadenosine and its derivatives, which are toxic to T lymphpcytes


What's the typical presentation of SCID?

an infant with oral candidiasis, extensive diaper ash and failure to thrive

susceptible to recurrent severe infections by lots of pathogens - candida, P jiroveci, pseudomonas, CMS, varicella, etc.


In SCID, death will occur in under a year without what treatment?

hematopoetic cell transplantation

(some have also been treated with gene therapy)


What happens in Wiskott-Aldrich Syndrome?

thrombocytopenia and eczema


What is the mutation in wiskott aldrich?

x-linked recessive mutation in the gene encoding the wiscott-aldrich syndrome protein, which is thought to link membrane receptors, like antigen receptors, to cytoskeletal elements

this means they get a depletion of T cells and low antibody to polysaccharide antigen (so low IgM)


What's the genetic abnormality in Chediak-higashi? What's the effect?

defect in the gene CHS1/LYST, which is a part of the BEACH family of vesicle-trafficking regulatory proteins

this means you don't get fusion of phagosomes and lysosomes in phagocytes, causing susceptibilty to infections


What will you see on a peripheral smear in chediak higashi?

giant cytoplasmic granules in leukocytes and platelets
(confirm with genetic testing)


What are some of the common causes of secondary immunodeficiency?

1. immunosuppressive therapy (for malignancy, autoimmune disease, bone marrow ablation before transplant, treatment of GVHD or organ rejection)
2. microbial infections (HIV/AIDs)
3. malignancy
4. disorders of biochemical homeostasis like diabetes, renal insufficiency, cirrhosis, malnutrition, etc.
5. autoimmune disease
6. severe burn injury
7. exposure to radiation or toxins
8. asplenia
9. aging


What sort of infections are people susceptible to if they don't have a spleen?

encapsulated organisms - strep pneumoniae, h influenzae, n meningitidis