Chapter 15: autoimmunity

homogenous

(FANA) -diffuse -pattern is characterized by uniform staining of the entire nucleus in interphase cells and of the condensed chromosomal region in metaphase cells -associated with antibodies to dsDNA, histones and DNP -found in patients with SLE, drug-induced lupus

RA etiology

-30 genetic regions -strongest association: subset of patients with RA and specific HLA-DRB1 alleles or PTPN22 gene polymorphism: POSITIVE FOR RHEUMATOID FACTOR (RF) or antibodies to CCP -strongest environmental risk factor: cigerette smoking which doubles the risk of the disease -infectious agents have been proposed as possible triggering antiges, but cause-effect relationship has not been proven

autoimmune thyroid diseases (AITDs)

-hasimoto's thyroiditis and Graves disease: share some antibodies in common both interfere with thyroid function thyroid gland: located in the anterior region of the neck and is normally between 12-20 grams in size -consist of units called follicles that are spherical in shape and lines with cuboidal epithelial cells -follicles filled with material called colloid 1. primary constituent of colloid is thyroglobulin (Tg): large iodinated glycoprotein from which the active thyoroid hormone triiodothyronine (T3) and its precursor thyroxine (T4) are synthesized 2. enzyme thyroid peroxidase (TPO): plays an important role in the synthesis of these hormones by oxiding iodine ions, allowing for their incorporation into the tyrosine residues of thyroglobulin to produce the building blocks for the hormones -normal conditons: synthesis of T3 and T4 is tightly regulated by an endocrine feedback loop called the thyroid axis

lab diagnosis of Hashimoto's

-have normal or high TSH levels and low FT4 levels -testing for thyroid antibodies: detected by sensitive ELISA and chemiluminescent immunoassays -antibodies to TPO are the best indicator of the disease because they are found in about 95% of patients, but only 10-15% of the general population -antibodies to Tg are less sensitive and specific because they are detected only 60-80% of patients with the disease and are found more frequently than TPO antibodies in healthy persons *negative test for Tg does not rule the disease

antiphopholipid antibodies

-heterogenous group of antibodies bind to phospholipids alone or phospholipids complexed with protein -can affect every organ in the body -associated with deep-vein and arterial thrombosis and with recurrent pregnancy loss -found: 60% of patients with lupus -identified: ability to cause false-positive results in nontreponemal tests fro syphilis, the lupus coagulant assay and immunoassays for antibodies to cardiolipin or other phospholipids *lupus anticoagulant: produced prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT) -patients with this antibodies the APTT may be prolonged by it not corrected by mixing with normal plasma -patients with this antibody have increased risk of clotting and spontaneous abortion -platelet function: may be also affected and thrombocytopenia may be present -factor assays: to rule out any factor deficiencies or factor specific inhibitors

antinuclear antibodies (ANAs)

-heterogenous group of antibodies that have diff. antigen specificities -nuclear antigens they are directed against include double-stranded (ds) and single-stranded (ss), DNA, histones, nucleosomes (DNA-histone complexes), centromere proteins and extractable nuclear antigens (ENAs) -autoantibodies directed against antigens in the nuclei of mammalian cells -95% of patients with active lupus -not specific for SLE -can also be detected in a significant percentage of patients with other connective tissue diseases, including mixed connective tissue disease, Sjogrens syndrome, scleroderma, polymyositis-dermatomyositis and RA -found in: individuals with other conditions such as chronic infections, cancer and pregnancy -5% of healthy persons and up to 30% of eldery individuals are ANA positive

fourescent antinuclear antibody (FANA) testing

-highly sensitive, detects a wide range of antibodies, inexpensive and easy to perform -antigens are in their original form and location within the cells -used as a screening test to identify patients who have ANAs to provide guidance in selection of follow-up assays based on immunoflourescence patterns and to monitor ANA titers in patients during treatment

lab diagnosis of T1D

-hyperglycemia -serological test: diabetes before beta cell destruction -tests for antibodies to GAD and IA-2A -if results negative: followed by ICA in children and for insulin antibodies in adults -ICAs have been reported in the sera of more than 80% of patients newly diagnosed with T1D -antibodies to islet cells: been detected by IIF using frozen sections of human pancreas -radio-immunoprecipitation assays, western blotting, ELISA and mass spectometry: used to detect antibodies other than pancreatic antigens such as insulin, GAD and IA-2 -combined screening for IA-2A, ICA and GAD: anitbodies appear to have the most sensitivity and best positive predictive value to T1D

treatment of RA

1;in the past it was based on nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylates (aspirin) and ibuprofen these agents can reduced local swelling and pain, they are not longer dominant treatment 2. disease-modifying anti-rheumatic drugs (DMARDs): notably methotrexate -methotrexate: act by inhibiting denosine metabolism and T-cell activation. If alone does not work it can be combine with DMARDs or with a biological agent 3. biological agents: target components of the immune system that are central to the pathogenesis of the disease 4. key therapies block the activity of TNF-alpha: *monoclonal antibodies to TNF-alpha *TNF-alpha receptors fused to an IgG molecule -all these agents specificially target and neutralize TNF-alpha and have demonstrated effectiveness in halting joint damage *DMARDS and biological agents: act on specific components of the inflammatory response and are effective in slowing the progression of joint erosion

autoimmune diseases

disorders in which immune responses are targeted toward self-antigens and result in damage to organs and tissues in the body -leading cause of chronic illness and death, affecting about 5% of the world's population including 50 million people in the U.S

ANCAs not diagnostic for AAV

disorders: types of vasculities, connective tissue diseases such as SLE and RA, autoimmune gastrointestinal and liver diseases, certain infections including HIV and hepatitis C, malignancy and other diseases -ANCAs directed toward neutrophil antigens other than PR3 or MPO can be detected by IIF -positive ANCA test can be combines with clinical manifestations and histological findings of biopsy tissue to make and accurate diagnosis

epitope spreading

expasion of the immune response to unrelated antigens

molecular mimicry

refers to the fact that many bacterial or viral agents contain antigens that closely resemble the structure or amino acid sequence of self-antigens -exposure to such foreign antigens may trigger immune responses that cross-react with similar self-antigens *ex: gram positive bacterium Streptococcus pyogens and rheumatic fever an autoimmune disorder that primarily affects the joints and the heart -some patients that have acquired scarlet fever or phatyngitis as a result of infection with S pyogenes will proceed to develop rheumatic fever if they are not treated adequately with antibiotics -symptoms: 2-4 weeks after the infection and are though to be caused by production of antibodies to the M protein and N-acetyl glucosamine components of the bacteria which cross-react with cardiac myosin causing damage to the heart

Thyrotropin-releasing hormone (TRH)

secreted by the hypothalamus to initiate the process that eventually causes releases of hormones from thyroid

CREST syndrome

subset of scleroderma named after its five major features: calcinosis, Raynaud's phenomenon, esophageal dysmotility, slecordactyly and telengiectasia -IIF assay: centromere antibodies produce discrete speckled staining in the nuclei of the cells

extractable nuclear antigens (ENAs)

-group of nuclear antigens that were so names bacause they were isolated in saline extracts of mamalian tissues -represent a family of small nuclear proteins that are associated with uridine-rich RNA -include: ribonucleoproteins (RNP), the Sm antigen, the SS-A/Ro and SS-B/La antigens, Scl-70, Jo-1 and PM-1

genes that influence the development and regulation of immune responses

1. PTPN22 gene: has a role in T and B cell receptor signaling 2. IL2RA gene: involved in T cell activation and maintenance of Tregs 3.CTLA4 gene: inhibitory effect on T cell activation 4. BLK gene: inhibitory effect on T-cell activation and devlopment 5.AIRE: promotes development of T cell tolerance in thymus

GPA antibodies

-80% the antibody is directed against an enzyme found in the auzurophilic granules of neutrophils called PR3 -antibody to the PR3 antigen play a role in the pathophysiology of the systemic vasculitis seen in GPA -events such as chronic infections can result in the release of the proinflammatory cytokine TNF-alpha which stimulates neutrophils and results in migration of the PR3 antigen from the granules to the neutrophil membrane -binding of PR3 antibodies to the PR3 antigen and Fcgamma-receptors on the cell surface result in activation of the neutrophils which adhere to the endothelial cells lining the blood vessels -release reactive oxygen species and proteolytic enzymes that damage the vascular endothelium -Th1 response follows, with the release of cytokines that induce macrophage maturation and the formation of granulomatous lesions -chronic activation of T cells: thought to induce differentiation of autoreactive B cells into plasma cells that produce antibodies to PR3, thus perpetuating the response

speckled

-FANA -characterized by discrete, flourescent specks throughout the nuclei interphase cells -staining is absent in the nucleolus and in the chromatin region in dividing cells -can be fine or coarse, depending on the autoantibody present -associated with antibodies to ENAs -found: patients w/SLE, Sjogren's syndrome, systemic sclerosis and other systemic autoimmune rheumatic diseases

nucleolar

-FANA -prominent staining of the nucleoli within the nuclei of interphase cells is seen in this pattern -size and shape and number of the nucleoli per cell are variable and staining can be smooth, clumpy or speckled, depending on the type of antibody present -staining may not be present in dividing cells -nucleolar pattern is primarily caused by antibodies to RNA and RNP and is seen mainly in patients with scleroderma

peripheral

-FANA -rim or outline -diffuse staining seen in through the nucleus -greater staining intensity around the outer circle surrounding the nucleus in interphase cell -dividing cells show strong staining of the condensed chromatin -primarily caused by antibodies to dsDNA and is highly specific for SLE

GPA genes involve

-HLA-DPB1*0401 allele has been found to have a strong association with GPA in caucasian patients -HLA-BRB1*0901 and HLA-DRB*1501 alleles are associated with increased risk in Asian and African American populations -environmental factors not been identified, chronic nasal infections with staphylococcus aureus bacteria has been associated with a greater rate of relapse in patients with EG -S aureus: induce molecular mimicry because it contains peptides that bear similarity to the proteinase 3 (PR3 autoantigen) -exposure to silica or certain drugs such as hydralazine and penicillamine may be also risk factors

centromere

-NAFA -numerous discrete speckles are seen in the nuclei of interphase cells and the chromatin of dividing cells -46 speckles, representing the number of chromosomes -pattern caused antibodies to proteins in the centromeres of the chromosomes and is found mainly in patients with the CREST syndrome

Granulomatosis with polyangiitis (GPA)

-Wegener's granulomatosis or WG -rare autoimmune disease involving inflammation of the small- to medium-sized blood vessels or vasculitis -begins with localized inflammation of the upper and lower respiratory tract -general symptoms include fever, malaise, arthralgias, anorexia and weight loss -symptoms: upper airway include severe or persistent rhinorrhea (runny nose), rhinitis, sinusitis, oral or nasal ulcers and gingivitis -damage to the nasal mucosal leads to drying of the nasal membranes, which become susceptible to infection and frequent bleeding -chronic otitis media: cause perforation and scarring of the eardrums, leading to hearing loss -tissue damage: perforation of the nasal septum or collapse of the bridge of the nose -patients can experience coughing, shortness of breath, chest pain or hemoptysis that may be asymptomatic -renal involvement: mild glomerulonephritis with little functional impairment to severe glomerulonephritis with little functional impairment to severe glomerulonephritis that can rapidly lead to kidney failure pain and arthritis of large joints -skin lesions -ocular manifestations: lead to vision loss -affect nervous system, heart, and thyroid gland -without treatment 90% of patients will die within 2 years of diagnosis

self-tolerance

-ability of the immune system to accept self-antigens and not initiate a response against them

Microsphere multiplex immunoassay (MIA)

-amenable to automated, high throughput testing with objective results -more efficient than ELISAs, allow for multiple testing antibody specificities to be performed in a single tube -variable in terms of their sensitivity and specificity when compared to IIF and that test performance varies with specific ANA detected 1.patient serum is incubated in a microtiter plate well containing a suspension of polystetyrene microspheres that are coated with individual nuclear antigens or with HEp-2 extract 2. beads containing specific antigens can be differentiated by their unique shade of red created by specific combination of infrared and red flourescence dye 3. antibodies in the patients serum will bind only to the beads containing their specified antigens 4. washing step to remove unbound antibodies, phycoerythrinlabeled anti-human IgG is added 5. conjugate will bind only to the beads that have bound patient anitbodies and excess conjugate is removed by washing 6. bead suspension if analyzed for flourescence by a flow cytometer that has two lasers, one that identifies each bead and another that detects the amount of flourescent conjugate attached

autoantibodies to noclear or nonnuclear

-antigens can also cause cellular destruction by other mechanisms -antibodies to RBCs: cause hemolytic anemia -antibodies to platelets: cause thrombocytoponia by antibody-mediated cytotoxic (type II) hypersensitivity -antibodies to endothelial cells: cause inflammation of the blood vessels and vascular damage in lupus, may be responsible for the vasculitis and neuropsychiatric symptoms -phospholipid antibodies: increased in misscarriage, stillbirth and preterm delivery in pregnant women with lupus

SLE etiology

-appears to originate from: 1.environmental factors: UV light, medications and infectious disease -exposure to sunlight: trigger of the photosensitive skin rashes seen in many lupus patients, trigger of the potosensitive skin rashes seen in many lupus patients *drugs: procainamide (used to treat abnormal hearth rhythms), hydralazine (used for high blood pressure) and tuberculosis drug isoniazid can induce transient lupus-like symptoms 2.hormones: estrogen containing contraceptives or hormone replacement therapy -may help regulate the transcription of genes that are central to the expression of SLE -20 genetic loci associated with lupus: -people with certain HLA: HLA-A1 and DR3 have been increased chance of developing lupus -group of genes: increased susceptibility to SLE plays a role in the clearance of immune complexes -other lupus associated genes: polymorphisms in genes associated with immune function, genes coding for various cytokines and genes involved in signaling of innate immune responses -defects: result in uncontrolled autoreactivity of T and B cells which leads to the production of numerous autoantibodies

Atineutrophil cytoplasmic antibodies (ANCAs)

-autoantibodies produced against proteins that are present in the neutrophil granules -associated with: GPA or WG, microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangititis (EGPA; Churg-Strauss syndrom) these syndromes are known as ANCA-associated vasculitides (AAV) -patients with GPA: ANCAS are mainly directed against the PR3 antigen whereas MPA and EGPA they are usually specific for myeloperoxidase (MPO)

celiac disease

-autoimmune disease affecting small intestine and other organs -affects 0.6-1.0% -gluten: protein complex found in wheat, barley and rye, that is poorly digested by the upper gastrointestinal system, contains alcohol-soluble component called gliadin that si rich in the amino acids glutamine and proline -gliadin resistant to digestive enzymes in the stomach, pancreas and small intestine and therefore remains intact in the lumen -if there is an increase in permeability of the intestinal wall possibly result of an infection, undigested gliadin is able to pass through the epithelial barrier of the intestine and trigger an appropriate immune response -immunogenicity of gliadin: enhances when acted on by tissue transglutamine (tTG) an intestinal enzyme that converts the glutamine residues in gliadin to glutamic acid -result in immunogenic peptides are generated that specifically react with HLA-DQ2 or HLA-DQ8 molecules on APCs -presence of these two haplotypes is necessary conditions for developing celiac disease -patients (90-95%) poses HLA-DQ2 allele whereas almost all of the remaining patients have HLA-DQ8 -gladin peptides are picked up by the APC are presented to antigen-specific CD4+ T cells which produce cytokines that activate CD8+ T cells and trigger inflammation response that damages the architecture of the intestinal mucosa and causes injury to the villi -B cells are stimulated to produce antibodies to the deaminated gliadin peptides (DGPs), tTG and endomysium

ELISA and CLIA

-automated, easy to perform and yield objective results -test for a broad range of antibodies if multiple nuclear antigens are coated onto a single test well -specific ANAs if each well is coated with single antigen -antigens: commercial kits derived from tissue extracts or are produced by recombinant tecnology -many labs used to screen for the prescence of ANAs in addition to identifying specific ANAs -large variation in the performance of tests produced by different manufacturers, which is influenced by the antigen preparation used *example: one study found sensitvities of this assay ranging from 69-89% and specificities from 81-98% when they were compared with IIF ANA method -may miss a significant proportion of ANA-positive patients and also yield a significant number of false-positive results

anticentromere antibodies

-bind to proteins in the middle region of a chromosome where the sister chromatids are joined -antibodies direct against three centromere antigens of m.w. 16kDa, 80kDa adn 120kDa -found: 50-80% of patients with CREST syndrome

RA immunopathology

-caused by an inflammatory process that results in the destruction of bone and cartilage -the lesions in joints show an increase in cells lining the synovial membrane and formation of a pannus, sheet of inflammatory granulation tissue that grows into joint space and invades the cartilage -infiltration of the inflamed synovium with T and B lumphocytes, plasma cells, dendritic cells, mast cells and granulocytes is evidence of immunologic activity within the joint -autoantibodies RF and anti-CP though to combine with their specified antigen and the resulting immune complexes become deposited in the joints resulting in a type III hypersent. -complement protein binds to the immune complexes, activating the classical component cascade -C3a and C5a are generated which act as chemotactic factors for neutrophils and macrophages leads to chronic inflammation which damages synovium itself

interactions between factors

-caused by complex interaction between genetic and environmental factors -certain genes make individuals more susceptible to immune responses to self-antigens but are not sufficient to cause an autoimmune disease -gender, tissue injury, and exposure to infections micros or other environmental agents can trigger autoimmune disease -immunologic tolerance, auto reactive T cells recognize and proliferate in response to self-antigens and B cells develop into plasma cells that secrete autoantibodies -result in release of proinflammatory cytokines, when coupled with dysfunctions in immune regulatory cells, perpeatuate the autoimmune responses -tissue injury results from hypersensitivity reaction that involve autoantibodies to cell surface receptors, deposition of immune complexes that contain self-antigens and cell-mediated cytotoxicity

microbata or normal flora in the immune system

-certain strains of endogenous bacteria may be associated with greater risk of autoimmune disease -may stimulate innate immune responses through interaction with TLRs -the interaction triggers cell-signaling pathways that result in the production of cytokines such as IFN-alpha which can stimulate cells of the adaptive immune system, some which are directed toward self-antigens -decrease in the number and function of Tregs can perpetuate the activity of autoreactive cytotoxic T cells and hyperactive B cells that produce autoantibodies -activated lymphocytes, produce proinflammatory cytokines that provide signals to stimulate cells of the innate system

hashimoto's thyroiditis

-chronic lymphocytic thyroiditis -autoimmune disease -women are 5-10 times more likely to develop the disease than men -patient develop: -enlarged tyroid called goiter, which is irregular and rubbery -thyroid-specific autoantibodies and cytotoxic T cells -immune destruction of the thyroid gland occurs, results in a state of decreased thyroid function called hypothyroidism -symptoms: dry kin, decreased sweating, puffy face with edematous eye-lids, pallor with yellow tinge, weight gain, fatigue and dry and brittle hair -classic form of disease: 1.thyroid shows hyperplasia with an increased number of lymphocytes -cellular types present include activated T and B cells, macrophages, and plasma cells -pathology: mediated primarily by CD8+ cytotoxic T cells, which bind to the thyroid cells and destroy them by releasing enzymes that cause apoptosis or necrosis -immune response results: development of germincal centers that almost completely replace the normal glandular architecture of the thyroid and progressively destroy the thyroid gland -antibodies to Tg and TPO: produced that have the ability to fix complement, result in an inflammatory response that perpetuates the tissue damage -injury of thyroid gland results: symptoms associated with hypothyroidism

systemic lupus erythematosus (SLE)

-chronic systemic inflammatory disease that affects between 40 and more than 200 persons per 100,000 -peak age: 20-40 years -more common in African american and hispanics than in caucasians -early diagnosis: 5-year survival rate has increased from 50% in the 1950s to great than 90% today

clinical criteria for lupus

-clinical critearia:acute cutaneous lupus, chronic cutaneous lupus, oral ulcers, non-scarring alopecia (thining of fragility of the hair), synovitis, serositis, renal involvement, neurological symptoms, hemolytic anemia, leukopenia and thrombocytopenia -six immunologic criteria: elevated antinuclear antibody titer, elevated anti-dsDNA titer, presence of antibody to the Sm nuclear antigen, presence of antiphospholipid antibody, low complement levels, and positive direct Coombs' test in the absence of hemolytic anemia -patient must satisfy at least 4 of 17 crieteria

lab diagnosis of lupus

-complete blood count (CBC), platelet count, urinalysis -lab findings: leukopenia and possible anemia and thrombocytopenia - erythrocyte sedimentation rate (ESR) may be elevated even thought the C-reactive protein (CRP) level tends to be low or normal -lab tests: quantification of complement proteins and the detection of specific autoantibodies -C3: most measured -serum complements level may be low during disease flares as a result of complement consumption by immune complexes -complement levels helpful: initial diagnosis but also monitoring patients over time

treatment of hasimotos disease

-daily oral thyroid hormone replacement therapy with levothyroxine (T4) -TSH levels should be monitored throughout treatment and are used in adjusting the dose of the drug so that normal TSH levels are maintained

IIF with Crithidia luciliae

-detect antibodies to dsDNA -purified antigen preparation that is free from single stranded DNA must be used because antibodies to ssDNA occur in many individuals with other autoimmune or inflammatory disease -uses organism Crithidia luciliae: trypanosome has a circular organelled called kinetoplast that is composed mainly of dsDNA 1.patient serum is incubated on a microsc. slide coated with C luciliae organisms and binding is detected with flourescent-labeled anti Ig conjugate 2. wash the slide after each step to remove unbound anitbody -positive test: brightly stained kinetoplast -high degree of specificity, less sensitive

SS-A/Ro and SS-B/La

-family of ENAs -consists of small, uridine-rich RNAs complexed to cellular proteins and given the prefix of SS- because a large percentage of patients with Sjogren's syndrome (70%) possess antibodies to the antigens *Anti-SS-A/Ro: 24-60% of patients with SLE and closely associated with the presence of nephritis, vasculitis, lymphadenopathy, photosensitivity and hemotalogic manifestations such as leukopenia *antibodies to SS-B/LA found: only 9% to 35% of patients with SLE all of this have anti-SS-A/Ro *SS-B/La antibody: found in patients who have cutaneous manifestations of SLE especially photosensitivity dermatitis -antibodies to both SSA/Ro and SS-B/La can cross the placenta and have been associated with neonatal lupus -newborns w/anti-SS-A/Ro: develop cardiac manifestations whereas those with anti-SS-B/La are skin lessions -to detect the presence of these antibodies in IIF: human tissue culture such as HEp-2 (human epithelial) must be used because SS-A/Ro and SS-B/La antigens are not found in mouse or rat liver and kidney -speckled pattern is evident -antibodies to the SS-A/Ro: detected on IIF if special cell line HEp-2000, these cells have been genetically transfected so that they hyperexpress the antigen

horror autotoxicus

-fear of self-poisoning 1990s Paul Ehrlich notes that the immune system could attack the very host is was intended to be protect

perinuclear or p-ANCA (ANCAs)

-fluorescence surrounds the lobes of the nucleus, blending them together so that individual lobes cannot be distinguished -pattern is caused by antibodies against positively charged antigens such as MPO that migrate out of the granules after ethanol fixation and are attracted toward the negatively charged nucleus -stain nuclei of the neutrophils

antihistamines antibodies

-found in lupus patients -histones are nucleoproteins that are essential components of chromatin -five major classes of histomes: H1, H2A, H2B, H3 and H4 -antibodies with H2A and H2B can detected in almost all patients with drug-induced lupus -presence of antihistone antibody alone or combined with antibody to ssDNA supports the diagnosis of drug-induced lupus -70% SLE have elevated levels of antihistone antibodies, titers are usually fairly low -high levels of antihistone antibodies: associated with more active and severe SLE -antihistome antibodies: found in RA, Felty's syndrome, Sjogren's syndrome, systemic slcerosis and primary biliary cirrhosis but levels are usually lower -antihistome antibodies: produce homogenous pattern in IIF assays

diabetes mellitus

-group of endocrine disorders characterized by hyperglycemia (high levels of glucose in the blood) -american diabetes association (ADA) three main categories 1. type 1: 5-10% of patients with diabetes mellitus are classified as having T1D -characterized by complete or nearly deficiency of insulin -90% have an immune-mediated form of the disease known as type 1A diabetes 2. type 2: characterized by insulin resistance and occurs most commonly in obese individuals over the age of 40 3. gestational diabetes: develops during pregnancy -type B: 10% idiopathic cases with no identifiable cause

Graves disease

-hyperthyroidism -women exhibit great susceptibility to Graves disease by a margin of about 5 to 1 and most often present with the disease in the fifth and sixth decades of life -excess of thyroid hormones, with a diffusely enlarged goiter that is firm instead of rubbery -clinical symptoms: nervousness, insomia, depressionm weight loss, heat intolerance, sweating, rapid heart beat, palpitations, breathlessness, fatigue, cardiac dysrhythmias and restlessness -35% of patients is exophthlamos: hypertrophy of the eye muscles and increased connective tissue in the orbit cause the eyeball to bulge out so that the patient has a large-eyed staring expression -evidence of orbital fibroblasts express TSH receptor like proteins that are affected by thyroid-stimulating Ig just as the thyroid -localized edema: lower legs tyroid: shows unform hyperplasia with a patchy lymphocytic infiltration -follicles have little colloid but are filled with hyperplastic epithelium -large number of these cells exhibit HLA-DR antigens on their surface in response to IFN-gamma produced by infiltrating T cells -allow presentations of self-antigens such as the thyrotropin receptor to activated T cells -B cells: stimulate to produce antibodies

ouchterlony test

-immunodiffusion -determine the immunologic specificity of a positive FANA test, particularly when a speckled pattern is observed -double diffusion detects antibody to several of the small nuclear proteins or ENA -antibodies: Sm, RNP, SS-A/Ro, SS-B/La, Scl-70 (DNA topoisomerase I) and Jo-1 1.solution containing ENA antigens is placed in a central well of an agarose plate and patient samples and controls are placed in the sorrounding wells 2. visible precipitate formed between the ENA well and each surrounding well that contains antibodies to any of the ENAs present 3. outer well does not contain antibodies to any of the ENAs, no precipitate is formed between that well and the center well 4. samples in the outer wells are indentified as containing antibody to a particular ENA by comparing their reactivity patterns of identity, nonindentity or partial identity to control sera containing specific ENA antibodies *positive reaction: indicated by immunoprecipitation lines of serological identity -not as sensitive as some other techniques

SLE immunopathology

-include antibodies to double stranded DNA (dsDNA), histones and other nuclear components, autobodies to lymphocytes, erythrocytes, platelets, phospholipids, ribosomal components and endothelium -typical patient: average of 3 circulating autoantibodies -B cell and autoantibodies: produce a central role in the pathogenic mechanisms that are responsible fir this complex disease -presence of autoantibodies: 9-10 years -abnormal apoptosis: releasing excess amounts of cellular constituents such as DNA and RNA -dysfunctional removal of cellular debris by phagocytes may allow these cellular components to persist increasing the chances of autoantibody production -antibodies to dsDNA: present 70% of patients with lupus -anti-dsDNA and complement proteins: been found in immune complexes that are deposited in organs such as the kidneys and skin and are thought to play a major role in the pathogenesis of SLE -accumulation of IgG to dsDNA: seems to be the most pathogenic because it forms complexes of an intermediate size that become deposited in the glomerular basement membrane (GBM) -immune complexes are formed they cannot be cleared efficiently because of other deficiencies in lupus patients 1.defects in complement receptors on phagocytic cells 2. defects in receptors for the Fc portion of Ig or rarely deficiencies of early complement components such as C1q, C2 or C4 -immune complexes activate complement and initiate and inflammatory response -leuckocytes are attracted to the sites of inflammation and release cytokines resulting in tissue damage

lab diagnosis for anti-CCP (RA)

-increased specificity for RA -ELISA: circular synthetic form of citrullinated peptides to increase test sensitivity, which ranges from 39% to 50% -about 20-30% of RF-negative patients are positive for anti-CCP and the presence of anti-CCP precedes the onset of RA by several years -prescence associated with an increased likelihood to develop clinically significant disease activity with a worse prognosis -specificity of anti-CCP for RA is higher than RF, ranging from 91-93% -combination of anti-CCP and RF testing has specificity of 98-100% providing a more accurate diagnosis of RA by allowing for better differentiation from other arthritis -pattern is speckled pattern direct against RNP

treatment for type I diabetes

-injectable insulin -clinical trials: immunosupressive drugs and biological agents to inhibit the autoimmune responses that lead to beta cell desctruction and prevent progression of disease -transplantation of pancreatic beta islet cells: who have poor glucose control requires continual immunosupressive therapy in order to prevent rejection -stem cells produce islet cells: vritro methods to induce immunologic tolerance in receptients

clinical signs and symtoms of RA

-intial symptoms: joints, tendon and bursae -patient experiences nonspecific symptoms: malaise, fatigue, fever, weight loss and transient joint that begin in the small joints of the hands and feet -joint stiffness and pain during the morning and improve during the day -disease can affect: knees, hips, elbows, shoulders and cervical spine -joint pain: muscle spams and limitation of motion -if ongoing inflamation left untreated results in permanently joint dysfunction and deformity -osteoporosis: 20-30% o -develop of extra-articular manifestations: smoking early disease onset and test positive for anti-CCP or RF *formation of subcutaneous nodules, pericalditis, lymphadenopathy, splenomegaly, interstitial lung disease or vasculitis -nodules:masses of tissue over the bones *found in myocardium, pericardium, heart valves, pleura, lungs, spleen and larynx diseases: 1. Sjogrens syndrome: develop in 10% of patients, autoimmune disease characterized by the presence of dry eyes and dry mouth in addition to connective tissue disease 2.felty's syndrome: combination of chronic nodular RA couple with neutropenia and splenomegaly -most common cause of death: cardiovascular disease, presumably because of the acceleration of arteriosclerosis by proinflammatory cytokines released during the diseases process

pos-translational modifications

-involve biochemical processes such as acetylation, lipidation, citrullination and glycosylation -these modifications can alter the immunogenicity of an antigen, affecting its ability to be processed by APCs and presented to T cells -such alterations of self antigens can make them more immunogenic, leading to autoimmune reponses -ex: citrullination of collagen might play a role in the pathigenesis of rehumatoid arthritis (RA) and glycosylation of myelin may be involved in the pathology of multiple sclerosis

type 1A diabetes

-juvenile onset diabetes: develops in children or in young adults before the age of 30 -chronic autoimmune disease that involves selective destruction of the beta cells of the pancreas -these cells are located in clusters called the islets of langerhans and are responsible for the production and secretion of the hormones, insulin -insulin: regulate the amount of glucose in the cirulation by promoting its absorption by skeletal muscles and fat tissue so that it can be converted into energy needed for our cells -autoimmune destruction of beta cells: results in insufficient insulin production, hyperglycemia and toxic effects on the body -long term effects: cardiovascular complications, renal disease, nerve damage, blindness and infections in lower extremeties can lead to amputations -patients require life long: insulin injection to control glucose levels and lower risk of these complications -inherited genetics: -HLA-DR3 or DR4 gene, and there is an increase risk when both of these genes are present -strong correlation: HLA-DQ haplotypes and type 1 -environemental influences: certain viral infections and early exposure to cow's milk

lab diagnosis for graves disease

-low or undetected levels of TSH and increased levels of FT4 -increased uptake of radioactive iodine also helps to confirm diagnosis -antibodies to TPO and Tg are found in the majority of patients -TRAbs: highly indicative of the disease, present 98-100% of patients *two types: 1. binding assays -automated solid-phase ELISA or chemiluminescent immunoassays labeled TRAb reagent competes with the patient antibody for TSH receptor bound to a solid phase 2. bioassays: tissue culture and thus are difficult to perform -detect the ability of TRAbs to bind to TSH receptors on live cells and trigger cAMP-dependent luciferase activity -these assays can distinguish between TRAbs with stimulatory activity versus those with inhibitory activity because they are functional assay

thyroid-stimulating hormone receptor antibodyes (TRAbs)

-major antibodies involved in the pathogenesis of graves disease -bind to the TSH receptor they mimic the action of TSH, resulting in uncontrolled receptor stimulation with excessive release of thyroid hormone -other antibodies present: anti-Tg, anti-TPO, thyrotropin receptor-blocking antibody -thyrotropin receptor-blocking: may coexit with thyroid-stimulating antibody in a number of patients -depending on the activity of blocking and stimulating autoantibodies, patient symptoms may vary from hyperthyroidism to euthyroidism to hypothyroidism which may cofound the patients diagnosis

RA indicators of inflammation

-measurement of ESR, CRP, complement components -typically ESR and CRP are elevated and the levels of serum complement components are normal or increased because of increased acute-phase reactivity -CRP levels reflect the intensity of the inflammatory response

lab dignosis for thyroid diseases

-measurement of circulating TSH levels -TSH levels are inversely related to the levels of T3 and T4 -TSH is routinely measured with high sensitive chemiluminescent immunoassays that can detect fewer than 0.1 mU/L -a normal TSH level indicated normal thyroid function -TSH level is abnormally high or low, lab tests for circulating thyroid hormones levels must be performed -useful to measure unbound thyroid hormones usually free T4 (FT4)

double stranded DNA (dsDNA) antibodies

-most specific for SLE because they are mainly seen in patients with lupus and their levels correlate with disease activity -found: 40-70% of patients the presence of these antibodies is considered diagnostic for SLE especially when they are found in combination with low levels of the complement component C3 -antibodies: produce peripheral or homogeneous staining pattern or indirect immunoflourescence (IIF)

lupus clinical signs and symptoms

-nonspecific symptoms such as fatigue, weight loss, malaise, fever and anorexia -marked by alternating relapses or flares and period of remission -90% patients develop polyarthralgias or arthritis: involves small joints of the hands, wrists and knees -skin manifestations: 80% of patients with lupus, an erythematous rash appear in any ares of the body expose to UV light -butterfly across the nose and cheeks: appers in SLE patients -renal involvement: nephritis is major cause of illness and death -dangerous: diffuse proliferative glomerulonephritis characterized by cell proliferation in the glomeruli that can lead to end-stage renal disease -kidneys: deposition of immune complexes in the subendothelial tissue and thickening of the basement membrane which can lead to renal fialure -cardiac involvement: pericarditis, tachycardia or ventricular enlargement, pleuritis with chest pain and neuropsychiatric manifestations such as seizures, mild cognitive dysfunction, psychoses or depression -hematologic abnormalities: anemia, leukopenia, thrombocytopenia or lymphopenia can also be present

cytoplasmic c-ANCA in ANCAs

-pattern primarily caused by PR3-ANCA and appears as a diffuse, granular staining in the cytoplasm of the neutrophils -staining is most intense in the center of the cell between the nuclear lobes and gradually fades at the outer edges of the cytoplasm -nuclear lobes may be more clearly seperated, speckled staining may be present and the nuclei of the lymphocytes will also be stained

genetics in autoimmune diseases

-prevalent in monozygotic (genetically identical twins) than dizygotic (non-identical) twins or siblings -association between the presence of certain human leukocyte antigen (HLA) types and the risk of developing a particular autoimmune disorder -strongest link found in B27 allele and the development of ankylosing spondylitis an autoinflammatory disease that affects the spine -HLA-B27: 100 greater chance of developing the disease than individuals who do not have that allele -differences in MHC genes are thought to influence the development of the MHC molecule can determine whether or not a self-antigen can attach to the peptide-binding cleft of the molecules and subsequently be processed and presented to T cells -class II MHC can abnormally expressed on cells where they are not typically found, resulting in the presentation of self-antigens for which no tolerance has been established -polymorphism in some non-MHC gene can be associated with development of autoimmune diseases -variance suggests that environmental and other factors also play a role in the development of autoimmune disease

type 1 diabetes immunopathology

-progressive inflammation of the islets of langerhans in the pancreas lead to fibrosis and destruction of most beta cells -hyperglycemia does not occur until 80% or more of the beta cells are destroyed -immunohistochemical staining of inflamed islets shows preponderance of C8+ lymphocytes, along with plasma cells and macrophages -B cells may acts as APCs stimulating activation of CD4+ lymphocytes -shift to Th1 response causes production of certain cytokines inlcuding TNF-alpha, IFN-gamma and IL-1 -inflammation: responsible for destruction of beta cells -islet autoantobodies trigger the immune response: no known what role they play in cell destruction -cell death: caused by apoptosis and attack by cytotoxic lymphocytes -autoantibody producyion precedes the development of T1D by months to several years -autoantibodies found: many of these antigen are components of the regulated pathway that is essential for the secretion of insulin: -insulinoma antigen 2 (IA-2), and IA-betaA (phogrin), anti-insulin antibodies, antibodies to the enzyme glutamic acid decardboxylase (GAD-65), antibodies to zinc transporter 8 (ZnT8) and antibodies to various other islet cell proteins, called islet antibodies (ICAs)

treatment for graves disease

-radiactive iodine: emits beta particles that are locally destructive within an area of few millimiters -iodine is administered for 1-2 years and results in a 30% to 50% long-term remission rate -some patients become hypothyroidal within 5 yrs Europe and japan: -patient placed first with beta blockers as adjuvant therapy -drug treatment, radioactive iodine therapy or surgery to remove part of the thyroid -surgery: recommended for patients resistant to drug, but can damage the laryngeal nerves and cause permanent hoarseness

immunilogic disorders

-results from loss of self-tolerance -state of immune unresponsiveness that is directed against a specific antigen

peripheral tolerance

-self-reactive lymphocytes manage to escape to the secondary lymphoid organs such as the lymph nodes and spleen 1. lymphocytes that recognize self-antigens in the secondary lymphoid organs are rendered incapable of reacting with those antigens 2. T cells can result from anergy caused by the absence of a costimulatory signal from an antigen-presenting cell (APC) or binding of inhibitory receptors such as CTLA-4 3. also can result from inhibition by Tregs or death by apoptosis, be rendered anergic after repeated stimulation with self-antigens or receive inhibitory signals through receptors such as CD22 *self-tolerance can fail even after this second layer of protection, autoimmunity can arise

nucleosome antibodies

-stimulated by DNA-histone complexes known as nucleosomes or DNA protein (DNP) -antibodies are directed only against the complexes and not against DNA or the individual histones -found: 85% of patients with SLE and their levels correlate with disease severity -IIF assay: produce homogenous pattern in the IIF assay

genes in thyroid

-strong association between HLA-DR3 and graves disease -Hashimotos with inheritance of HLA antigens DR3, DR4, DR5 and DQ7 -unique feature of both: HLA-DR antigens are expressed on the surface of thyroid epithelial cells -mutations in the thyroid globulin gene: allow for interaction of the protein with HLA-DR antigens, resulting in antithyroglobulin antibodies (found in both) -graves modifications in the TSH receptor gene: allow immune system to recognize the receptors and produce antibodies against it environmental triggers: -infections, certain medications, smoking, physyological stress and pregnancy -strongest link: high iodine intake and development of hashimotos disease -highly iodinated thyrogobulin is more immunogenic, creating or exposing more epitopes and facilitating the antigen uptake and processing step of the adaptive immune response

therapy for GPA

-suppression of this inflammatory response -severe forms treated with a combination of prednisone and cyclophosphamide which produced remission with resolution of the inflammatory lesions in most patients -biological agents anti-CD20 monoclonal antibody rituximab show effective alternative to cyclophosphamide with reduced toxicity -infections are the main cause of death in about half of GPA -immunosupressive therapy: survival rates as high as 80% at 10 years after diagnosis

rheumatoid arthritis (RA)

-systemic autoimmune disease -affects: 0.5-1.0% of adult population -varies with ethnicity and geographic location -ages of 25-55 -highest in women who are more than 65 years of age -characterized as chronic, symmetric and erosive arthritis of the peripheral joints that can also affect multiple organs such as the heart and the lungs -progresses to joint deformity and disability -reduced life exptancy

limitations of FANA

-time consuming and requires significant amount to identify the flourescent pattern

positive in ANA screen

-titer >=160 generally considered be clinically significant -serially diluted and tested to determine the antibody titer, specified as the higher dilution to show nuclear flourescence

ANA testing

-using HEp-2 cells as the substrate in IIF should be negative -test can be repeated using microsc. slides with formalin fixed lukocytes *formalin: cross-linking fixative that prevents the migration of antigens out of the granules -in the presence of antibodies to MPO or other positively charged proteins, perinuclear staining will be prevented and intense, granular staining of the cytoplasm will be seen that resembles c-ANCA -ANCA detection by IIF: sensitvity of more than 90% for the AAV, lower specificity (80% or less) because ANCAs, especially those producing the p-ANCA pattern can be found in other conditions -samples that are positive: through initial testing with IIF should be confirmed by PR3 and MPO specific immunoassays whenever possible -assays: automated ELISA, chemiluminescence immunoassay and flourescent EIA formats -combination of automated immunoassays and IIF: ANCAs can be detected nearly 100% of patients with activem systemic GPA -failure to detect ANCAs:does not rule out the presence of AAV -ANCAs titer: useful for monotoring disease activity, but are limited value in predicting relapses in patients who are remision

hormonal influence

-women are 2.7 times more likely to acquire an autoimmune disease than men -females have been found to have higher absolute CD4+ T-cell counts and higher levels of circulating antibodies than men -hormonal influence of the development of autoimmunity -studies on the effects of hormones have shown that estrogens tend to direct the immune system in favor of a type 2 helper cell (Th2) response, resulting in more B-cell activation and antibody production -androgens favor type 1 helper cell (Th1) response with activation of CD8+ T cell -prolactin a hormone that stimulates production of breast milk in pregnant and nursing women, can stimulate both humoral and cell mediated immune responses -stimulatory effects of female hormones may place women at a greater risk for developing autoimmune disease

lab diagnosis of RF (RA)

1. RF: IgM class that reacts with the Fc portion of IgG -70-90% of patients with RA test positive for RF -negative result does not rule the presence of RA -psotive result: RF is present in about 5% of healthy individuals and in 10-25% of those over the age of 65 -found: in patients with other connective tissue diseases such as SLE, Sjogren's syndrome, scleroderma and mixed connective tissue disease and some chronic infections -manual agglutinations test using charcoal or latex coated with IgG used to detect RF -tests: only detect IgM isotype found in about 75% of patients and have been largely replaced by ELISA, chemiluminescence immunoassay and nephelometric methods which are automated have greater precision and sensitivity and can also detect other RF isotypes -presence of both IgM and IgA rarely occurs -IgM RF levels: decrease with clinical responses to therapy and that elevation of IgA early in the disease appears to be associated with a poor response to TNF-alpha inhibitors and a worse prognosis

two key antibodies found in RA

1. RF: antibody that is most often of the IgM class and is directed against the Fc portion of IgG -play a role in the pathogenesis of RA by increasing macrophage activity and enhancing antigen presentation to T cells by APCs 2. anti-CCP: second major type of antibody -citrullinated proteins contain an atypical amino acid called citrulline which is generated when the enzyme peptidyl arginine deiminase (PAD) modifies the amino acid arginine by replacing an NH2 group with a neutral oxygen -enzyme is associated with granulocytes, monocytes and macrophages -death of granulocytes and macrophages triggers production of citrullinated poteins -overexpression of these antigens may provoke an immune response in individuals with certain HLA-DRB1 alleles -these antibodies can react with citrulline-containing components of the matrix including filaggrin, keratin, fibrinogen and vimentin and are thought to correlate with the pathogenesis of RA

patient sera screened for ANCAS steps

1. ethanol-fixed leukocytes as the cellular substrates 2. ethanol treatment permeabilizes the granule membranes, allowing for migration of the contents 3. patient serum incubated with a microscope slide containing ethanol-fixed leukocytes 4. incubation, slide is washed to remove unbound serum and an anti-human IgG, FITC-labeled conjugate is added 5. second incubation and wash step the slide is viewed under flourescent microscope for staining of the neutrophils 6. lymphocyte staining should not be present, it should be minimal

criteria for type 1 diabetes

1. fasting glucose greater than 126 mg/dL on more than one occasion (normal value is lower than 100 mg/dL) 2. random plasma glucose level of 200 mg/dL or more with classic symptoms of diabetes 3. an oral glucose tolerance test of 200 mg/dL or more in a 2-hour sample with a 75 g glucose load 4. hemoglobin A1c value (HbA1c) greater than 6.5% -HbA1c is glycated form of hemoglobin that is made when the RBC protein combines with glucose in the blood -HbA1c plasma level: proportional to the life span of circulating RBCs (120 days) and reflects the average plasma glucose concentration over previous 2-3 months

FANA steps

1. microscope slide onto which nucleated cells have been fixed 2. human epithelial cell line, HEp-2 is the standard substrate for clinical labs 3. HEp-2 cells are used because they have large nuclei with high antigen expression, allowing for high sensitivity and facilitating visualization of results 4. patient serum is incubated with the HEp-2 cell-coated slide washes to remove unbound antibodies and then allowed to react with an anti-human Ig labeled with flourescent tag to detect bound IgG or total Ig 5. second incubation and wash 6. slide mounted and viewed under a flourescent microscope using 400X magnification 7. screening test performed with a 1:40 or 1:80 dilution of patient serum in order to avoid detecting low positive titers that may be seen in healthy persons 8. inclusion of 1+ end-point contorl serum can help to standardize the readings by setting the minimum level of flourescence that is considered positive 9. pattern of flourescence reported: provide clues about the autoantiboy present and associated diseases -flourescen can be within nucleus, cytoplasm or mitotic structures of the cell

GPA criteria published by the ACR

1. nasal or oral inflammation with oral ulcers or purulent or bloody nasal discharge 2.abnormal chest x-ray showing presence of nodules, fixed infiltrates or cavities 3.urinary sediment with microhematuria or RBC casts 4. granulomatous inflammation on biopsy -positive antineutrophil cytoplasmic antibody (ANCA)

central tolerance

1. occurs in central or primary lymphoid organs, the thymus and the bone marrow 2. T cells mature in the thymus, they encounter self-antigens that are normally present of the surface of the thymic epithelial cells 3. negative selection, T cells that express T cell receptors (TCRs) with a strong affinity for these self-antigens are deleted by apoptosis 4. negative selection occurs with both the immature, double-positive CD4+/CD8 cells in the cortex and with the more mature, single-positive CD4+ or CD8+ cells in the medulla 5. some of the self-reactive CD4+ T cells are not deleted, but instead differentiate into Tregs cells that can specifically inhibit immune responses to self-antigens 6. B cells mature in the bone marrow, those with receptors having a strong affinity for self-antigens are eliminated by apoptosis 7. some self-reactive B cell are not deleted: rather they are stimulated to rearrange their immunoglobulin genes so that their B-cell receptors are no longer antigen specific, this process known as receptor editing 9. B cells that possess receptors that only weakly recognize self-antigens are induced to downregulate the expression of their receptors and develop a specific state of unresponsiveness to the antigens known as anergy

lupus treatment

1.mild symtoms: high dose of aspirin or other anti-inflammatory drug may bring relief 2. skin manifestations: antimalarials such as hydroxychroroquine or chloroquine and topical steroids are often prescribed -antimalarial drugs: inhibit signaling of TLR 7, 8, and 9 -systemic corticosteroids: used for acute fulminant (several or sudden), lupus nephritis or central nervous system (CNS) complications because these supress the immune response and lower antibody titers 3.monoclonal antibodies and other biological agents: target components of the immune system thought to be central to pathogenesis of lupus are being evaluated for their clinical effectiveness 4.prevent organ damage and achieve remission -most common cause of death: infection followed by heart disease -5 year survival rate has increased to 90%

diagnostic classification criteria for RA

1987 -based on the number of joints involved, durantion of symptoms, serology results for RF and anti-CCP, serum level of the acute-phase reactant, CRP and the ESR

Thyroid Stimulating Hormone (TSH)

TRH acts on the pituitary gland to induce release of... -TSH binds to receptors on the cells of the thyroid gland causing thyroglobulin to be broken down into secretable T3 and T4 -level os T3 and T4 become too high, they feed back to the hypothalamus and pituitary to inhibit release of TRH and TSH, resulting in decreased production of the thyroid hormones -presence of autoantibodies to components of the thyroid gland interferes with this process and causes under or overactivating of the gland

Anti-RNP antibody

against RNP -consists: several nonhistone proteins complexes to a small nuclear RNA called U1-nRNP (U for uridine-rich) -forms complexes with the Sm antigen in the nucleus and antisera to these antigens produce a pattern of partial idenditity when they are reacted in the Ouchterlony double immunodiffusion test -IIF assay: produces coarse speckled pattern -detected 20-30% of patients w/SLE -found at a high titer in individuals with mixed conenctive tissue disease and lower levels in patients with other autoimmune rheumatic diseases such as systemic sclerosis, Sjogrens syndrome and RA

Sm antigen

antibody specific for lupus because it is not found in other autoimmune diseases -20-40% of patients with SLE -unclear whether titers correlate with disease activity -described in patient named Smith -produces a coarse speckled pattern of nuclear flourescence on IIF

microbial infections

development of autoimmune disease -bacteria, viruses and other infectious pathogens

-proinflammatory cytokines in RA

found in synovial fluid that contribute to inflammation IL-1, IL-6, IL-17 and TNF-alpha -TNF-alpha plays a key role in the inflammatory process by stimulating the production of other cytokines and facilitating the transport of WBCs to the affected areas -trigger the release of matrix metalloproteinases from fibroblasts and macrophages; these enzymes degrade important structural proteins in the cartilage

autoantibodies

harmful effects can be caused by T-cell-mediated immune responses or... -directed against host antigens

epigenetics

modifications in gene expression that are not caused by changes in the original DNA sequence -these alterations are stable and can be inherited -though to be triggered by exposure to environmental toxins, ingestion of harmful foods or drugs or the aging process -can induce changes by increasing or decreasing methylation of cytosine bases, modifying histones and causing abnormal regulation by microRNAs -these modifications result in changes in the level at which genes are expressed by affecting their ability to be transcribed into mRNA which is translated into proteins that will influence the phenotype of an individual -over or underexpression of certain genes in the immune system may result in homoestatic imabalances and breakdown of self-tolerance, leading to autoimmunity

local bone erosion in RA

multinucleated giant cells called osteoclasts are central to the structural damage that is seen in the bones -osteoclasts absorb bone as part of the normal bone remodeling process that occurs in the body response to growth and repair damaged of bone -osteoclasts become overly activated in the inflammatory environment of joints -TNF-alpha in conjunction with other cytokines and a molecule called RANKL (receptor activator factor kappa-B ligand) induced the differentiation of osteoclasts and inhibits bone formation -local bone destruction occurs and there is also generalized osteoporosis throughout the body

FANA test negative

no clearly discernable flourescent pattern is observed, in the nuclei of the cells -5% of SLE patients are negative this test cannot be used to rule out SLE

lab diagnosis of GPA

normochronic, normocytic anemia, leuckocytosis, esosinophilia and elevated ESR -decreased concentration of albumin in the blood and mild to severe renal insufficiency -urinalysis typically shows microhematuria, proteinuria and cellular casts -selogical findings: elevated CRP, elevated immunoglobulin levels, positive ANCAs and possibly autoantibodies such as RF and ANAs

neonatal lupus

occurs up to 8% of babies born to pregnant women with SLE -associated with antibodies to the nuclear antigens SS-A/Ro and SS-B/La -symptoms: 6-8 months of age when the maternal antibodies have cleared from the infants circulation -in utero heart block: serious complication that occurs in 2% of fetuses whose monther have an anti-SS-A antibodies

mixed patterns in FANA

pattern may totally or partially obsecure another -titration of the patient serum can help to distinguish between the separate patterns and an antibody titer would be reported for each one

nucleolus

prominent structure within the nucleus where transcription and processing of ribosomal RNA and assembly of ribosomes takes places -staining of the nucleolus in IIF caused by antibodies to one of three nucleolar components: fibrillarin, RNA polymerase I and PM-1 -antibody to fibrillarin: systemic sclerosis and is indicated by clumpy nucleolar flourescence in the IIF assay -scleroderma: autoimmune disease that primarily involves the skin and the blood vessels -antibodies to RNA polymerase associated with sleroderma produce a speckled nuclear pattern in IIF -homogenous staining of the nucleolus is associated with antibodies to the PM-1 antigen -found: polymyositis and systemic slcerosis

superantigens

proteins that are produced by various microbes that have the ability to bind to both class II MHC molecules and TCRs, regardless of antigen specificity -ex: staphylococcal enterotoxins that cause food poisoning and toxic shock syndrome -can act as potent T-cell mitogens by activating a large number of T cells with different antigen specificities -if some of these T cells posses specificity for a self-antigen, autoimmune responses might result -viruses: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause polyclonal activation of B cells

drug induced lupus

symptoms ussually disappear once the drug is discontinued -common drugs: procainamide, hydralazine, chlorpromazine, isonaizid, quinidine, anticonvulsants such as methyldopa and possibly oral contraceptives -manifested: fever, arthritis or rashes; rarely are the kidney involve

bystander effect

the microbial organisms does not have to share structurally similar antigens with the host -micro can induce a local inflammatory response that recruits leukocytes and stimulates APCs to release cytokines that nonspecifically activate T cells -some of the T cells that are activated may have specificity for self-antigens

tissue trauma and release of cryptic antigens

when immunologic tolerance to self-antigens occurs during the early development of lymphocytes in the thymus and bone marrow, some self-antigens may be cryptic or hidden within the tissue of the host -inflammation or tissue trauma could cause the cryptic antigens to be released and to suddenly be accessible to the unducated lymphocytes, triggering an immune response -tissue damage could be caused by factors such as infections, contact with environmenttal toxins or physical injury from exposure to UV radiation -immunologic ignorance: responsible for the production of autoantibodies to the lens of the eye following an ocular injury, autoantibodies to sperm after a vasectomy and autoantibodies to DNA following damage to skin cells by overexposure to UV rays to the sun