Hypersensitivity, Tolerance, Autoimmunity, & Immune Disorders

Describe Rheumatoid Arthritis and its symptoms

-Chronic, SYMMETRIC, erosive arthritis of peripheral joints in adults. Most patients have Rheumatoid Factors. -Activation of Th1/Th17 CD4+ Tcells which release inflammatory mediators and cytokines + TNFa which leads to destruction of the joints and other tissues. Typically small joints affected earlier in disease -Associated with HLA-DR gene Symptoms: -Ulnar deviation -Swan neck deformity -Pes Planus -Pulmonary nodules

What lab results would you expect from a RA patient?

-Diffuse salmon pink evanescent rash -Swollen, tender MCP joints -Anemia (decrease in RBC) -Leukocytosis (INCREASE in WBC) -Thrombocytosis (INCREASE in platelets) -RF+ & anti-CCP+ & SSA+ & ASO+ -Protein in urine

Describe DiGeorge Syndrome, the prototypic Tcell disorder.

-Dysmorphic facies -Congenital heart disease -Hypocalcemia (hypoparathyroidism) -Depressed Tcell immunity (no thymus)

What lab results would you expect from an SLE patient?

-Leukopenia (decrease in WBC) -Anemia (decrease in RBC) -Thrombocytopenia (decrease in platelets) -Blood and Protein in urine -Prolonged PTT -ANA=anti-dsDNA (renal involvement) & anti-Sm -Anti-phospholipid antibodies

Describe the nature of allergens in Immediate Hypersensitivity

-Low molecular weight -low dose sensitization (favors IL-4 production via Th2 cells) -Highly soluble and stable -Peptides that bind to MHC II (CD4+ Th cells)

Describe a Type III Hypersensitivity reaction

-Pathologic hallmark of Necrosis and PMN infiltration -Macrophages also stimulated to release TNF-α and IL-1. Severity of disease is dependent upon the ability to clear the complexes

Describe the (3) steps associated with how immune complexes are deposited and mediate pathology

1) Immune complexes interact with cells via complement and Fc receptors to stimulate the release of VASOACTIVE AMINES 2) VA Amines cause endothelial cell retractions, ^^ Vascular permeability, allowing deposition of immune complexes on vessel walls 3) Platelets aggregate on exposed collagen which form microthrombi

What are the (2) different types of mast cells and what Inflammatory Mediators are released from Activated Mast Cells?

1) Mucosal Mast Cells- produce tryptase 2) Connective Tissue Mast Cells- produce tryptase, chymase Granule Associated Mediators: Histamine, Tryptase, Chymase, Carboxypeptidase, Heparin, Chondroitin sulfate E Lipid Derived Mediators: Prostaglandin D2 (PGD2)- Unique to mast cells; Leukotrienes, Platelet activating factor Cytokines/Chemokines: Interleukins 3, 4, 5, 13; GM-CSF; TNF-some stored pre-formed in granules); chemokines-CCL3

Since Central tolerance is not 100% effective, what (3) ways is Tolerance in self-reactive T cells in the periphery dealt with?

1) Tcell Anergy 2) Tcell Ignorance 3) Treg suppression

What is the mechanism of immune complex deposition

1. Antigen-Antibody complexes formed in blood vessels. IgG and IgM are the only antibodies involved. May vary in size from small soluble complexes to large insoluble complexes 2. Complexes bind complement by the classical pathway 3. TNF-α and IL-1 produced by macrophages, both of which may cause tissue damage and recruit PMN's 4. Complement components, C5a, C3a, and C4a cause release of vasoactive amines (histamine, 5-hydroxytrypamine) from both mast cells and basophils which cause increase in vascular permeability to occur which permits additional complexes to be deposited in the vessel wall 5. Complexes induce platelet aggregation and complement activation. Platelets aggregate to form microthrombi on exposed collagen of basement membrane 6. PMN's are attracted to site by chemotactic factors associated with complement activation (C3a, C5a). C5a increases adherence of PMN's to vessel wall. They are not able to ingest complexes but nevertheless release their lysosomal enzymes which cause further damage to the vessel wall. 7. Release of enzymes and tissue damage cause fever, pain in local site (joints, kidney, peripheral blood vessels)

Describe Serum Sickness

1. Disease process is initiated by injection of large amount of Ag into patient who has not been exposed to the Ag previously. 2. Ag level in blood drops quickly in first 2-3 days due to equilibration of Ag between vascular and intravascular spaces (equilibrium phase) 3. Ag level then declines slowly until days 9-10. Normal catabolism of Ag; rate of decline dependent on chemical and physical properties of Ag (exponential phase). 4. Ab begins to develop about days 5-6. Immediately complexes with Ag, so cannot be detected free in serum. Complexes are soluble because of Ag excess in blood. Major immunoglobulins involved in complexes are IgG and IgM. 5. Complement causes release of vasoactive amines from platelets. Vasoactive amines increase vascular permeability. 6. Complexes deposited and damage occurs. Splenomegaly and lymphadenopathy develop because of intense immune response. 7. As more Ab produced, larger complexes are formed. Large complexes activate complement more efficiently and cause binding of complexes to red blood cells via C3b and the CR1 receptor on red blood cells. The cells and attached complexes are then removed in the liver and spleen. Ag is thus rapidly removed from blood. Free Ab can be detected in serum (immune phase). 9. Disease subsides as Ag cleared from system. Serum sickness is never fatal.

In regards to Immediate Hypersensitivity, define a Basophil and its role

A circulating cell of bone marrow origin that enters tissues and responds to danger signals of innate and acquired immunity with release of inflammatory mediators. -Derived from myeloid precursors, contain granules that stain with basic dyes such as hematoxylin. -Like Mast cells express FcRI constitutively on cell surface -recruited to site of allergic response and degranulate by antigen cross-linking FcRI on cell surface. Inflammatory mediators are similar to mast cells, except basophils do not produce PGD2.

Fibromyalgia--pathophysiology

A number of abnormalities in pain processing have been demonstrated in fibromyalgia. Among them are the following: Excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate levels in the insula) Low levels of inhibitory neurotransmitters (eg, serotonin and norepinephrine) in descending anti-nociceptive pathways in the spinal cord Maintained enhancement of temporal summation of second pain Altered endogenous opioid analgesic activity in several brain regions known to play a role in pain modulation Dopamine dysregulation

In regards to Immediate Hypersensitivity, Define a Mast Cell, its origin, its specific GF and GF-receptor

A tissue based inflammatory cell of bone marrow origin that responds to danger signals of innate and acquired immunity with immediate and delayed release of inflammatory mediators. Bone marrow derived immature mast cells circulate in blood as agranular forms, and then settle in tissues near small blood vessels. Mast cells present in all vascularized tissues except central nervous system and retina. Origin: CD 34+ Pluripotent stem cells Primary growth factor: Stem cell factor (SCF) Growth factor receptor: CD117(kit) -Maturation process is driven by stem cell factor (SCF) interacting with CD117 (kit). During maturation in tissues, characteristic granules form

What is Central Tcell Tolerance and what occurs during its (2) steps?

AKA T cell clonal deletion, is designed to ensure the development of mature T cells that are restricted to self-MHC (i.e. recognize peptides in association with self-MHC), but are specific for foreign antigens rather than self-antigens. T cell central tolerance occurs in the thymus Step 1. Positive selection: Promotes the survival of thymocytes with self-MHC restricted T cell receptors (TCR) Step 2. Negative selection: Promotes the elimination of thymocytes that are self-MHC restricted, but are specific for self-antigens

ACR classification criteria for Sjogren syndrome In comparison with commonly used AECG criteria, the ACR criteria are based entirely on a combination of objective tests that assess the three main components of Sjögren syndrome (serologic, ocular, and salivary) and do not include criteria based on subjective symptoms of ocular and oral dryness. Application of these criteria has yielded a sensitivity of 93% and a specificity of 95% for the diagnosis of Sjögren syndrome. These criteria do not distinguish between primary and secondary forms of Sjögren syndrome.

According to the ACR criteria, the diagnosis of Sjögren syndrome requires at least two of the following three findings: Positive serum antiSSA and/or antiSSB antibodies or positive rheumatoid factor and antinuclear antibody titer of at least 1:320 Ocular staining score of at least 3 Presence of focal lymphocytic sialadenitis with a focus score of at least 1 focus/4 mm in labial salivary gland biopsy samples

Sjogren Syndrome--classification

According to the AmericanEuropean classification system (as modified by Tzioufas and Voulgarelis), diagnosis of primary Sjögren syndrome requires at least four of the criteria listed below; in addition, either criterion number 5 or criterion number 6 must be included. Sjögren syndrome can be diagnosed in patients who have no sicca symptoms if three of the four objective criteria are fulfilled. The criteria are as follows: 1. Ocular symptoms Dry eyes for more than 3 months, foreignbody sensation, use of tear substitutes more than 3 times daily 2. Oral symptoms Feeling of dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing 3. Ocular signs Schirmer test performed without anesthesia (< 5 mm in 5 min), positive vital dye staining results 4. Oral signs Abnormal salivary scintigraphy findings, abnormal parotid sialography findings, abnormal sialometry findings (unstimulated salivary flow < 1.5 mL in 15 min) 5. Positive minor salivary gland biopsy findings 6. Positive anti-SSA or anti-SSB antibody results Secondary Sjögren syndrome is diagnosed when, in the presence of a connective tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5, above.

Describe the process of Tcell Anergy, a type of peripheral Tcell Tolerance

Anergy is a process by which MATURE CD4+ and probably CD8+ cells are inactivated to antigen stimulation, but are not deleted. Anergy in T cells is induced when the T cell encounters antigen presented by an APC such as a resting B cell that expresses MHC molecules, but lacks the costimulation molecules (e.g. B7) needed to fully activate the T cell. Anergic CD4+ cells are unable to produce IL-2 in response to antigen challenge, and therefore fail to expand

Describe Recruitment and activation of inflammatory cells in a Type II hypersensitivity response

Antibody (IgG and IgM) attaches to host tissue and results in fixation of complement by classical pathway. PMN's attracted to site by complement, attach to fixed antibody by Fc piece, and release enzymes which cause tissue damage. PMN's may also recognize C3b which will have attached to host tissue after complement activation An example of this mechanism is Goodpasture's syndrome in which autoantibodies develop to lung and glomerular basement membranes

Describe a Type II Hypersensitivity reaction

Antibody-dependent cell-mediated cytotoxicity (ADCC) 1. Antibody (IgG, IgM) attaches to antigen on host cell. Natural killer (NK) cells bearing Fc receptors attach to the exposed Fc region on the bound antibody. NK cells destroy target cells by direct contact but are not themselves destroyed in the process. Macrophages may also function similarly in an ADCC reaction. Host cells may be killed if antibody is directed against viral antigens associated with the cell. 2. ADCC may also be mediated by IgE and IgG with eosinophils as the effector cell in the same manner. However, this combination does not normally result in host tissue damage and is primarily a defense mechanism in infections.

What occurs upon reexposure and what symptoms do you expect from a Type I Hypersensitivity?

Antigen-specific IgE bind and cross-link the FceRI, resulting in a signal cascade that resulting in immediate release of inflammatory mediators such as histamine, tryptase, and TNFa from intracellular granules. Initial degranulation is then followed by synthesis of other inflammatory mediators such as leukotrienes, prostaglandins and cytokines, which result in a late phase response approximately 6-8 hours after the immediate reaction. During the late phase response, inflammatory cells such as eosinophils and Th2 lymphocytes are recruited into the site Symptoms= sneezing, rhinorrhea, cough, wheezing, vomiting diarrhea, or systemic anaphylaxis.

What is the definition of Immune Tolerance?

Antigen-specific immunologic unresponsiveness, and represents the block in the development, proliferation or effector function of specific T cells and B cells. It is designed to prevent an immune response to self-antigens (i.e. autoimmunity).

Guillain-Barre Syndrome--autonomic changes

Autonomic changes in GBS can include the following: Tachycardia Bradycardia Facial flushing Paroxysmal hypertension Orthostatic hypotension Anhidrosis and/or diaphoresis Urinary retention

Parental history of substance addiction may increase likelihood of developing arthritis

Children who grew up with a drug or alcohol addicted parent were at significantly increased risk for developing arthritis in adulthood. After adjustment for demographic characteristics, socioeconomic status, adult health behaviors, mental health conditions, and adverse childhood experiences, the odds ratio for developing arthritis among subjects with an addicted parent was 1.30 (95% CI: 1.12 1.51).

The Myasthenia Gravis Foundation of America Clinical Classification divides MG into 5 main classes and several subclasses

Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IIIb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both; use of a feeding tube without intubation Class V: Defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management

Describe phagocytosis and complement-mediated cell lysis in a Type II Hypersensitivity response

Complement lytic pathway may also result in damage to host tissue. This occurs in hemolytic anemias such as Hemolytic Disease of the Newborn. Phagocytosis of antibody-coated cells - Antibody and C3b may opsonize tissue cells and effect killing or phagocytosis of the cells as they come into contact with phagocytic cells, particularly, macrophages in spleen or liver

Describe a Type IV Hypersensitivity reaction

Dependent upon CD4 Th1 cells and macrophages. IFN-γ secreted by Th1 cells activates macrophages. Both Th1 cells and macrophages secrete TNF-α which is responsible for much of pathology Ex: TB, Rheumatoid arthritis, contact dermatitis (poison ivy)

Fibromyalgia--pain sensitivity in women Fibromyalgia is most common in women, it is thought that women may have mechanisms that contribute to increased sensitivity to pain.

Differences in primary afferent input to the CNS, with developmental and menstrual cycle-dependent enhancement Developmental and phasic gonadal-hormonal modulation of pain regulatory systems, stress-induced analgesia, and opioid receptors Higher levels of trait and state anxiety Increased prevalence of depression Use of maladaptive coping strategies Increased behavioral activity in response to pain

What is the difference between SLE and DLE?

Discoid Lupus Erythematosus -limited to skin -not a systemic disease -ANA may be present, but dsDNA and Sm antibodies are typically absent

What is frequently seen (but not exclusively) in homogeneous nuclear pattern F-ANAs?

Drug induced Lupus (DiL)

Rheumatoid Arthritis--DMARDs

Early therapy with DMARDs has become the standard of care; it not only can more efficiently retard disease progression than later treatment but also may induce more remissions. Many of the newer DMARD therapies, however, are immunosuppressive in nature, leading to a higher risk for infections. Nonbiologic DMARDS include the following: Hydroxychloroquine Azathioprine Sulfasalazine Methotrexate Leflunomide Cyclosporine Gold salts Dpenicillamine Minocycline Biologic TNF-inhibiting DMARDs include the following: Etanercept Infliximab Adalimumab Certolizumab Golimumab Biologic non-TNF DMARDs include the following: Rituximab Anakinra Abatacept Tocilizumab Tofacitinib

Myasthenia Gravis--patient education

Educate patients to recognize and immediately report impending respiratory crisis. Intercurrent infection may worsen symptoms of MG temporarily. Mild exacerbation of weakness is possible in hot weather. The risk of congenital deformity (arthrogryposis multiplex) is increased in offspring of women with severe MG. Certain medications (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, betablockers, procainamide, and quinidine) may exacerbate symptoms of MG; many others have been associated only rarely with exacerbation of MG. Patients should always consult a neurologist before starting any of these medications. Statins may cause worsening of myasthenia without regard to type of MG or brand of statin.

Sjogren Syndrome--patient education

Educate patients with Sjögren syndrome on avoidance strategies and selfcare issues for the treatment of dry mouth, eyes, skin, and vagina. Patient education pamphlets regarding the disease are available through the Arthritis Foundation

Sjogren Syndrome--complications

Emergence of disorders associated with Sjögren syndrome, such as SLE and RA Infection of the parotid gland, typically staphylococcal, streptococcal, or pneumococcal clues include unilateral worsening of symptoms, along with tenderness, warmth, and erythema Emergence of parotid tumors watch for unusually hard or unilateral parotid enlargement Pregnant patients with antiRo/SSA antidodies are at risk for fetal loss, complete heart block in the fetus, and neonatal lupus syndrome in the newborn Emergence of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin Bcell lymphomas

In regards to Immediate Hypersensitivity, define an Eosinophil and its role

Eosinophils are bone marrow derived granulocytes, the majority of which reside in tissues while minority circulating in blood; activation of eosinophils by external stimuli leads to staged release of inflammatory mediators. Mediators are highly toxic and kill invading microorganisms and parasites directly, followed by slower induction and synthesis of prostaglandins, leukotrienes and cytokines, which amplify immune response -In resting state eosinophils DO NOT express FcRI, and must be activated by other inflammatory signals to induce receptor expression. -Hypereosinophilic syndromes are complicated by neuropathy and endomyocardial damage resulting from toxicity of eosinophil mediators

What is the Etiology and findings associated with Sjogren's Syndrome?

Etiology: -Autoimmune disorder characterized by destruction of exocrine glands (lacrimal and salivary) by lymphocytes -Can be a 2nd-dary syndrome associated with RA Findings: -Inflammatory joint pain -Decreased tear and salvia production -Bilateral Parotid enlargement -SSA/SSB antinuclear antibodies

What is the Etiology, joint findings, presentation, and treatment of Rheumatoid Arthritis?

Etiology: -Autoimmune inflammatory destruction of synovial joints mediated by cytokines and Type III & IV hypersensitivity reactions Joint Findings: -Granulation tissue formation in joints (MCP, PIP) -Ulnar deviation of fingers, swan neck deformities -80% have Rheumatoid Factor (anti-IgG Ab). Strong association with HLA-DR4 Presentation: -Morning stiffness, symmetric joint involvement -Fever, fatigue, weight loss, Pleuritis, pericarditis Treatment: -NSAIDs, glucocorticoids, Methotrexate, TNFa inhibitors

What is the distinguishing features of DiL in comparison to SLE?

Features essentially indistinguishable from SLE -Homogeneous pattern ANA NOTE: Has Ab to histone proteins (but not dsDNA or Sm)

Fibromyalgia--diagnosis

Fibromyalgia is a diagnosis of exclusion and patients must be thoroughly evaluated for the presence of other disorders that could be the cause of symptoms before a diagnosis of fibromyalgia is made. The clinical assessment may reveal objective evidence for a discrete or comorbid illness, such as the following: Hypothyroidism Rheumatoid arthritis Systemic lupus erythematosus Polymyalgia rheumatic Other inflammatory or autoimmune disorders Serious cardiac conditions in those with chest pain, dyspnea, and palpitations Although patients with fibromyalgia do not have characteristic or consistent abnormalities on lab testing, routine lab and imaging studies can help to rule out diseases with similar manifestations and to assist in diagnosis of certain inflammatory diseases that frequently coexist with fibromyalgia. Such tests include the following: Complete blood count with differential Metabolic panel Urinalysis Thyroidstimulating hormone level 25hydroxy vitamin D level Vitamin B12 level Iron studies, including iron level, total iron binding capacity, percent saturation, and serum ferritin level Magnesium level Erythrocyte sedimentation rate Antipolymer antibody assay: May provide conclusive evidence for a subgroup of people with fibromyalgia; about 50% of fibromyalgia patients have antipolymer antibodies

Fibromyalgia At a clinical level, fibromyalgia is much more than widespread pain. It overlaps substantially with other central sensitivity syndromes, such as the following: Chronic fatigue syndrome Irritable bowel syndrome Chronic pelvic pain syndrome/ primary dysmenorrhea Temporomandibular joint pain Tension-type headaches/migraine Post-traumatic stress disorder (PTSD) Multiple chemical sensitivity Periodic limb movement disorder/ restless legs syndrome Interstitial cystitis Fibromyalgia also overlaps with other regional pain syndromes and mood and anxiety disorders.

Fibromyalgia is a disorder of chronic, widespread pain and tenderness. It typically presents in young or middle-aged women but can affect patients of either sex and at any age. Fibromyalgia is a syndrome that consists of the following signs and symptoms: Persistent (≥ 3 mo) widespread pain (pain/tenderness on both sides of the body, above and below the waist, and includes the axial spine [usually the paraspinus, scapular, and trapezius muscles]) Stiffness Fatigue; disrupted and unrefreshing sleep Cognitive difficulties Multiple other unexplained symptoms, anxiety and/or depression, and functional impairment of activities of daily living (ADLs)

Guillain-Barre Syndrome--pathophysiology GBS is considered to be a postinfectious, immune-mediated disease targeting peripheral nerves. Up to two thirds of patients report an antecedent bacterial or viral illness prior to the onset of neurologic symptoms. Respiratory infections are most frequently reported, followed by gastrointestinal infections.

GBS is a post-infectious, immune-mediated disease. In several studies, C jejuni was the most commonly isolated pathogen in GBS. The virulence of C jejuni is thought to be based on the presence of specific antigens in its capsule that are shared with nerves. Cytomegalovirus (CMV) infections are the second most commonly reported infections preceding GBS, with CMV being the most common viral trigger of GBS. Vaccinations have been linked to GBS by temporal association. For example, a study reviewing GBS cases during the 1992-1993 and 1993-1994 influenza seasons found an adjusted relative risk of 1.7 cases per 1 million influenza vaccinations. In most cases, however, no definite causal relation has been established between vaccines and GBS (with the exception of rabies vaccine prepared from infected brain tissue and the 1976 swine flu vaccine). In a case-controlled study, patients with GBS reported more frequent penicillin and anti-motility drug use and less frequent oral contraceptive use. However, no definite cause-effect relationships have been established. Pathologic findings in GBS include lymphocytic infiltration of spinal roots and peripheral nerves (cranial nerves may be involved as well), followed by macrophage-mediated, multifocal stripping of myelin.

Guillain-Barre Syndrome--diagnosis Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most widely recognized form of GBS in Western countries The annual US incidence of GBS is 1.2-3 per 100,000 inhabitants, making GBS the most common cause of acute flaccid paralysis in the United States.

GBS is generally diagnosed on clinical grounds. A basic peripheral neuropathy workup is recommended in cases in which the diagnosis is uncertain. Biochemical screening can also be conducted and would include the following studies: Electrolyte levels Liver function tests (LFTs) Creatine phosphokinase (CPK) level Erythrocyte sedimentation rate (ESR) Needle EMG and nerve conduction studies Signs of demyelination can include the following: Nerve conduction slowing Prolongation of the distal latencies Prolongation of the F-waves[1, 2] Conduction block or dispersion of responses: Evidence frequently demonstrated at sites of natural nerve compression Weak muscles showing reduced recruitment: Demonstrated with needle examination (electromyography [EMG])

Rheumatoid Arthritis--genetic factors

Genetic factors account for 50% of the risk for developing RA. About 60% of RA patients in the US carry a shared epitope of the human leukocyte antigen (HLA)DR4 cluster, which constitutes one of the peptide binding sites of certain HLADR molecules associated with RA

What (4) factors may increase susceptibility to autoimmune disease?

Genetics: HLA plays an important role in autoimmune disease but so does HLA-independent factors Environmental factors are important in autoimmune etiology

Myasthenia Gravis--prognosis (morbidity & mortality)

Given current treatment, which combines cholinesterase inhibitors, immunosuppressive drugs, plasmapheresis, immunotherapy, and supportive care in an intensive care unit (ICU) setting (when appropriate), most patients with MG have a nearnormal life span. Mortality is now 34%, with principal risk factors being age older than 40 years, short history of progressive disease, and thymoma; previously, it was as high as 30-40%. In most cases, the term gravis is now a misnomer. Morbidity results from intermittent impairment of muscle strength, which may cause aspiration, increased incidence of pneumonia, falls, and even respiratory failure if not treated. In addition, the medications used to control the disease may produce adverse effects. Today, the only feared condition arises when the weakness involves the respiratory muscles. Weakness might become so severe as to require ventilatory assistance. Those patients are said to be in myasthenic crisis. The disease frequently presents (40%) with only ocular symptoms.

Describe what histamine does and its role in hypersensitivity

Histamine binds three types of receptors, H1, H2, and H3. Acute allergic reactions involve histamine binding to H1 receptors resulting in biologic effects such as increased vascular permeability, contraction of smooth muscle, and increased mucus secretion by epithelial linings. Effects depend on tissue exposed to allergen- i.e. sneezing/rhinitis vs. wheezing vs. vomiting/diarrhea

Describe Sensitization in Hypersensitivity reactions

Immediate hypersensitivity reactions occur in sensitized individuals. Allergic sensitization requires an initial exposure to antigen that generates an adaptive immune response and production of antigen specific IgE. After the primary immune response and clearance of the antigen, the IgE that has not encountered antigen, binds with high affinity to the FcRI on the surface of mast cells, basophils, and activated eosinophils The binding affinity of IgE to the FcRI is the highest of any isotype and can be considered for all practical purposes as irreversible. Mast cells and basophils constitutively express the FcRI and eosinophils express the receptor following cytokine activation

Myasthenia Gravis--pathophysiology

In MG, there is a reduction in the number of AChRs available at the muscle endplate and flattening of the postsynaptic folds. Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be produced, and they may fall below the threshold value for generation of an action potential. The end result of this process is inefficient neuromuscular transmission. Various drugs may induce or exacerbate symptoms of MG, including the following: Antibiotics (eg, aminoglycosides, polymyxins, ciprofloxacin, erythromycin, and ampicillin) Penicillamine This can induce true myasthenia, with elevated antiAChR antibody titers seen in 90% of cases; however, the weakness is mild, and full recovery is achieved weeks to months after discontinuance of the drug Betaadrenergic receptor blocking agents (eg, propranolol and oxprenolol) Lithium Magnesium Procainamide Verapamil Quinidine Chloroquine Prednisone Timolol (ie, a topical betablocking agent used for glaucoma) Anticholinergics (eg, trihexyphenidyl) Neuromuscular blocking agents (eg, vecuronium and curare) These should be used cautiously in myasthenic patients to avoid prolonged neuromuscular blockade

Rheumatoid Arthritis--exam

In most patients with RA, onset is insidious, often beginning with fever, malaise, arthralgias, and weakness before progressing to joint inflammation and swelling. S/S of rheumatoid arthritis may include the following: Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature) Progressive articular deterioration Extraarticular involvement Difficulty performing activities of daily living (ADLs) Constitutional symptoms The physical examination should address the following: Upper extremities (metacarpophalangeal joints, wrists, elbows, shoulders) Lower extremities (ankles, feet, knees, hips) Cervical spine During the physical examination, it is important to assess the following: Stiffness Tenderness Pain on motion Swelling Deformity Limitation of motion Extraarticular manifesta

Sjogren Syndrome--epidemiology

In the United States, Sjögren syndrome is estimated to be the second most common rheumatologic disorder, behind SLE. Sjögren syndrome affects 0.14% of the population. This wide range, in part, reflects the lack of uniform diagnostic criteria. Internationally, comparative studies between different ethnic groups have suggested that Sjögren syndrome is a homogeneous disease that occurs worldwide with similar prevalence and affects 12 million people. The female-to-male ratio of Sjögren syndrome is 9:1. Sjögren syndrome can affect individuals of any age but is most common in elderly people. Onset typically occurs in the fourth to fifth decade of life.

Juventile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA), is a heterogeneous group of diseases that differs markedly from adult RA. JIA is known to have genetically complex traits in which multiple genes are important for disease onset and manifestations, and it is characterized by arthritis that begins before the age of 16 years, persists for more than 6 weeks, and is of unknown origin.

How does Sjogren's Syndrome present on the eye?

Keratoconjunctivitis Sicca

Myasthenia Gravis--epidemiology

MG is uncommon. The estimated annual US incidence is 2 per 1,000,000. The prevalence of MG in the United States ranges from 0.5 to 14.2 cases per 100,000 people. This figure has risen over the past 2 decades, primarily because of the increased lifespan of patients with MG but also because of earlier diagnosis.

SLE--management

Management of SLE often depends on the individual patient's disease severity and disease manifestations, although hydroxychloroquine has a central role for longterm treatment in all SLE patients. Medications used to treat SLE manifestations include the following: Biologic DMARDs (diseasemodifying antirheumatic drugs): Belimumab, rituximab, IV immune globulin Nonbiologic DMARDS: Cyclophosphamide, methotrexate, azathioprine, mycophenolate, cyclosporine First line treatment for SLE: Nonsteroidal antiinflammatory drugs (NSAIDS; eg, ibuprofen, naproxen, diclofenac) Corticosteroids (eg, methylprednisolone, prednisone) Antimalarials (eg, hydroxychloroquine) Provide good patient education: Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light. Also, encourage them to receive non-live vaccines during stable periods of disease, to quit smoking, and to carefully plan pregnancies.

What happens immediately upon exposure to antigen in immediate hypersensitivity? Over minutes? Hours?

Mast cell IgE-dependent release of -Histamine -TNFa -Proteases -Heparin

What is CREST? How is it related to Scleroderma?

Milder form

What is Morphea?

Morphea is scleroderma limited to the skin - ANA is typically not present Problems when on face and around joints (causes immobility)

SLE--mortality

Mortality in patients with SLE has decreased over the past few decades. Prior to 1955, the 5-year survival rate in SLE was less than 50%; currently, the average 10-year survival rate exceeds 90%, and the 15-year survival rate is approximately 80%. Previously, mortality was due to the disease itself; currently, mortality is often a result of medication side effects (eg, fatal infections in individuals receiving potent immunosuppressive medications) or cardiovascular events. The European League Against Rheumatism (EULAR) task force also identified the following co-morbidities as increasing the risk of morbidity and mortality in patients with SLE: Infections Hypertension Lipid disorders (dyslipidemia), atherosclerosis, and coronary heart disease Diabetes mellitus Bone-related conditions: Osteoporosis; avascular bone necrosis Malignancies such as non-Hodgkin lymphoma, lung cancer, and hepatobiliary cancer

Describe PSS, aka, Systemic Sclerosis/Scleroderma to the best of your ability

Multi-system connective tissue disorder. Tissue fibrosis, vascular lesions. Fingertip pitting, skin thickening and shininess. Pulmonary Fibrosis. Calcinosis Cutis deposits in fingers. -Speckled or Nucleolar pattern ANA (Scl-70) -Concern about constrictive cardiac disease (renal disease less likely)

Describe MHC Class II Deficiency. What is its mutated gene?

Mutation in CIITA or RFX transcription factor genes -low CD4+ -normal CD8+

Describe MHC Class I Deficiency. What is its mutated gene?

Mutation in TAP -lack of CD8+ Tcells

Rheumatoid Arthritis--diagnosis

No test results are pathognomonic; instead, the diagnosis is made by using a combination of clinical, laboratory, and imaging features. Potentially useful laboratory studies in suspected RA include the following: Erythrocyte sedimentation rate (ESR) Creactive protein level (CRP) Complete blood count (CBC) Rheumatoid factor assay Antinuclear antibody assay (ANA) Anti−cyclic citrullinated peptide and anti−mutated citrullinated vimentin assays Potentially useful imaging modalities include the following: Radiography (first choice): Hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine, and other joints as indicated Magnetic resonance imaging: Primarily cervical spine Ultrasonography of joints: Joints, as well as tendon sheaths, changes and degree of vascularization of the synovial membrane, and even erosions Joint aspiration and analysis of synovial fluid may be considered, including the following: Gram stain Cell count Culture Assessment of overall appearance

Fibromyalgia--treatment Fibromyalgia is a chronic relapsing condition. There is no cure for fibromyalgia, but education, lifestyle changes, and proper medications can help the individual to regain control and achieve significant improvement. Education is an essential element in fibromyalgia management. The patient should be encouraged to foster self-efficacy, and healthcare providers should work to diminish dependence over time. Providers can help by teaching patients about the following: Identifying triggers of flare-ups Sleep hygiene Diet Physical activity recommendations including stretching, resistance, and aerobic activity

Non-pharmacotherapy: Diet (eg, promote good nutrition, vitamin supplementation, bone health, weight loss) Stress management Aerobic exercise (eg, low-impact aerobics, walking, water aerobics, stationary bicycle) Sleep therapy (eg, education/instruction on sleep hygiene) Psychologic/behavioral therapy (eg, cognitive behavioral, operant behavioral) Pharmacotherapy: Always combine pharmacologic and nonpharmacologic therapy in the treatment of fibromyalgia. Aggressively treat comorbid depression. Medications used in the management of fibromyalgia include the following: Analgesics (eg, tramadol) Antianxiety agents (eg, alprazolam, clonazepam, zolpidem, zaleplon, Trazodone, buspirone, temazepam, sodium oxybate) Skeletal muscle relaxants (eg, cyclobenzaprine) Antidepressants (eg, amitriptyline, duloxetine, milnacipran, venlafaxine, desvenlafaxine) Anticonvulsants (eg, pregabalin, gabapentin, tiagabine) Alpha 2 agonists (eg, clonidine) Other agents used in fibromyalgia may include: Vitamins and minerals Malic acid and magnesium combination Antioxidants Amino acids Herbs and supplements If nonpharmacotherapy fails to improve sleep problems, the following medications may help: Antidepressants (eg, trazodone, SSRIs, SNRIs, tricyclic antidepressants) Anticonvulsants (eg, clonazepam, gabapentin, tiagabine) Nonbenzodiazepine hypnotics (eg, zolpidem, zaleplon, eszopiclone) Muscle relaxants (eg, cyclobenzaprine, tizanidine) Dopamine agonists (eg, pramipexole)

Rheumatoid Arthritis--treatment

Optimal care of patients with RA requires an integrated approach that includes nonpharmacologic therapies and pharmacologic agents such as nonbiologic and biologic diseasemodifying antirheumatic drugs (DMARDs), nonsteroidal antiinflammatory drugs (NSAIDs), analgesics, and corticosteroids. Other drugs used therapeutically include the following: Corticosteroids Nonsteroidal antiinflammatory drugs (NSAIDs) Analgesics Surgical treatments include the following: Synovectomy Tenosynovectomy Tendon realignment Reconstructive surgery or arthroplasty Arthrodesis

Rheumatoid Arthritis--prognosis It's important to educate the pt about prognosis and treatment. Patients and families do best when they know what to expect and can view the illness realistically. Many patients fear crippling consequences and dependency.

Outcome in RA is compromised when diagnosis and treatment are delayed. The clinical course of RA is generally one of exacerbations and remissions. Approximately 40% of patients with this disease become disabled after 10 years, but outcomes are highly variable. It has been shown that intervention with DMARDs in very early RA (symptom duration < 12 weeks at the time of first treatment) gives the best opportunity for attempting to achieve disease remission. A common misconception is that a medication must be expensive to be helpful. Generic NSAIDs, low dose prednisone, and the first line DMARDs are quite inexpensive yet remarkably effective for relieving symptoms, a point that bears emphasizing. The belief that one must be given the latest TNF inhibitor to be treated effectively can be addressed by a careful review of the overall treatment program and the proper role of such agents in the patient's plan of care.

What are some distinguishing features of Sjogren's Syndrome?

Pathologically: Lymphocyte infiltrate in salivary glads

Guillain-Barre Syndrome--management (for FNPs)

REFER ASAP (pt needs tx in ICU) In primary care setting, we can educate patient about helpful therapies (i.e. physical, occupational, and speech therapy). Addressing upright tolerance and endurance may be a significant issue during the early part of physical rehabilitation. Active muscle strengthening can then be slowly introduced and may include isometric, isotonic, isokinetic, or progressive resistive exercises. Occupational therapy professionals should be involved early in the rehabilitation program to promote positioning, posture, upper body strengthening, range of motion (ROM), and activities that aid functional self care. Speech therapy is aimed at promoting speech and safe swallowing skills for patients who have significant oropharyngeal weakness with resultant dysphagia and dysarthria.

How does SLE test against dsDNA and Sm antibodies? WHat is likely in SLR?

Renal disease likely

What are Rheumatoid Factors? How do they react as autoantibodies?

Rheumatoid factors consist primarily of IgM or IgG antibodies specific for the Fc portion of self IgG High titers can be used to diagnose patients with Rheumatoid Arthritis and other systemic autoimmune diseases (SLE, Scleroderma, Sjogren's) High frequency of false positives, and low specificity

SLE--pathophysiology

SLE is an autoimmune disorder characterized by multisystem inflammation with the generation of autoantibodies. Although the specific cause of SLE is unknown, multiple factors are associated with the development of the disease, including genetic, epigenetic, ethnic, immunoregulatory, hormonal, and environmental factors. Many immune disturbances, both innate and acquired, occur in SLE More than 90% of cases of SLE occur in women, frequently starting at childbearing age. The use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease. The female-to-male ratio peaks at 11:1 during the childbearing years. A correlation between age and incidence of SLE mirrors peak years of female sex hormone production. Onset of SLE is usually after puberty, typically in the 20s and 30s, with 20% of all cases diagnosed during the first 2 decades of life

What is always present in Sjogren's Syndrome and why is it important in pregnancy?

SSA/SSB autoantibodies -Speckled pattern ANA NOTE: Can be present in conjuction with RA

Fibromyalgia--self-report forms for assessment **need to document all self-report forms

Self-report forms, for assessing patients' pain, fatigue, and overall status, include the following: Modified Health Assessment Questionnaire Fibromyalgia Impact Questionnaire Checklist of current symptoms Scales for helplessness and cognitive performance The Physician Health Questionnaire 9 for depression The Generalized Anxiety Disorder 7 ?aire for anxiety The Mood Disorder ?aire to screen for bipolar disease

Guillain-Barre Syndrome--prognosis The following factors have been associated with adverse effect on outcomes in GBS : Preceding gastrointestinal infection or diarrheal illness Older age (57 years or older) Poor upper extremity muscle strength Acute hospital stay of longer than 11 days ICU requirement Need for mechanical ventilation Medical Research Council (MRC) score below 40 Discharge to rehabilitation

Short of death, the worst-case scenario in GBS is tetraplegia within 24 hours, with incomplete recovery after 18 months or longer. The best-case scenario is mild difficulty walking, with recovery within weeks. The usual scenario, however, is peak weakness in 10-14 days, with recovery in weeks to months. Average time on a ventilator (without treatment) is 50 days. A 2008 epidemiologic study reported a 2-12% mortality rate despite ICU management,[60] although the rate may be less than 5% in tertiary care centers with a team of medical professionals who are familiar with GBS management. Causes of GBS-related death include acute respiratory distress syndrome (ARDS), sepsis, pneumonia, venous thromboembolic disease, and cardiac arrest. Most cases of mortality are due to severe autonomic instability or from the complications of prolonged intubation and paralysis. Numerous papers have addressed the issue of persistent fatigue after recovery from GBS. Studies have suggested that a large percentage of patients continue to have fatigue-related problems, subsequently limiting their function at home and at work, as well as during leisure activities. Treatment suggestions range from gentle exercise to improvement in sleep patterns to relief of pain or depression, if present. Recurrence of Guillain-Barré syndrome is rare but has been reported in 2-5% of patients.

Sjogren Syndrome--prognosis

Sjögren syndrome carries a generally good prognosis. In patients who develop a disorder associated with Sjögren syndrome, the prognosis is more closely related to the associated disorder (eg, SLE, lymphoma). Morbidity associated with Sjögren syndrome is mainly associated with the gradually decreased function of exocrine organs, which become infiltrated with lymphocytes. The increased mortality rate associated with the condition is primarily related to disorders commonly associated with Sjögren syndrome, such as SLE, RA, and primary biliary cirrhosis. Patients with primary Sjögren syndrome who do NOT develop a lymphoproliferative disorder have a normal life expectancy. Children born to mothers with antibodies against SSA/Ro are at an increased risk of neonatal lupus and congenital heart block. If one such child develops congenital heart block, the risk for congenital heart block during a subsequent pregnancy is 15%.

Sjogren Syndrome Primary Sjögren syndrome occurs in the absence of another underlying rheumatic disorder, whereas secondary Sjögren syndrome is associated with another underlying rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma

Sjögren syndrome is a systemic chronic inflammatory disorder characterized by lymphocytic infiltrates in exocrine organs. Most individuals with Sjögren syndrome present with sicca symptoms, such as xerophthalmia (dry eyes), xerostomia (dry mouth), and parotid gland enlargement. Numerous extra-glandular features may develop, such as: Arthralgia Arthritis Raynaud phenomenon Myalgia Pulmonary disease Gastrointestinal disease Leukopenia Anemia Lymphadenopathy Neuropathy Vasculitis Renal tubular acidosis Lymphoma About 50% of patients with Sjögren syndrome have cutaneous findings, such as dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria

Fibromyalgia--sleep dysregulation Almost all patients with fibromyalgia sleep poorly—hence, the common report that a night of poor sleep is followed by a more painful day. Indeed, intrusion of alpha waves into slow delta wave stage III/IV (deep) sleep was the first objective abnormality observed in fibromyalgia. Although not the proximate cause of fibromyalgia, abnormal sleep affects both limbs of the stress response system and contributes to negative mood and cognitive difficulties.

Sleep dysfunction is considered an integral feature of fibromyalgia. About 70% of patients recognize a connection between poor sleep and increased pain, along with feeling unrefreshed, fatigued, and emotionally distressed. Sleep can be divided into 2 main parts: non-rapid eye movement (NREM) and rapid eye movement (REM), which alternate cyclically through the night, always starting with NREM sleep. In each successive cycle through the night, NREM sleep decreases, and REM sleep increases. Each cycle, NREM plus REM, lasts about 90 minutes. NREM is divided into 4 stages: Stage 1 is initial drowsiness Stage 2 is light sleep Stages 3 and 4 are progressively deeper levels of sleep.

Describe Polymyositis/Dermatomyositis

Symptoms: -Progressive symmetric muscle weakness, inflammation with CD8+ Tcells, usually in the shoulders -Autoimmune attack of the muscles and skin causing weakness -Malar rash (similar to SLE) Findings: -ANA+, anti-Jo1+, anti-SRP+, anti-Mi-2 Ab's -Speckled pattern ANA Treatment: -Steroids followed by Methotrexate

What are the common Symptoms, Lab Findings, and Treatment of SLE? Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean manifestations and follows a relapsing and remitting course. More than 90% of cases of SLE occur in women, frequently starting at childbearing age.

Symptoms: -Rash, Joint pain, Fever, Hematologic disorders, Oral/nasal ulcers, Renal disease, Raynaud phenomenon, Photosensitivity, Neurologic disorders (seizures, psychosis) Findings: -ANA (antinuclear antibodies) -Positive VDRL/RPR test -Anti-dsDNA antibodies -Anti-Smith antibodies (directed against snRNPs) -Antihistone antibodies (drug induced Lupus) -Decreased C3, C4 due to immune complex formation -Increased Ab production with autoantibody formation (Th2) -Abs to RBC, WBC, and platelets -Abs to proteins complex to phospholipids (^risk of blood clot formation and prolonged clotting) Treatment: -NSAIDs, steroids, immunosuppressants, hydroxychlorquine

Describe what TNFa does and its role in hypersensitivity

TNFa promotes inflammation, stimulates cytokine secretion by other cell types, activates endothelium, and increases adhesion molecule expression which recruits leukocytes to inflamed tissues.

Describe a Type I Hypersensitivity reaction: What exactly occurs, what is released, what is required, and how fast it occurs

Th2 type response after primary exposure

Guillain-Barre Syndrome--epidemiology

The annual US incidence of GBS is 1.2-3 per 100,000 inhabitants, making GBS the most common cause of acute flaccid paralysis in the United States. No racial preponderance exists GBS has a male-to-female ratio of 1.5:1; male preponderance is especially seen in older patients. However, a Swedish epidemiologic study reported that GBS rates decrease during pregnancy and increase in the months immediately following delivery. In the US, the syndrome's age distribution seems to be bi-modal, with a first peak in young adulthood (ages 15-35 y) and a second, higher one in middle-aged and elderly persons (ages 50-75 y). Infants appear to have the lowest risk of developing GBS.

Myasthenia Gravis--diagnosis

The anti-acetylcholine receptor (AChR) antibody test for diagnosing MG has the following characteristics: High specificity (up to 100%) Positive in as many as 90% of patients who have generalized MG Positive in only 50-70% of patients who have purely ocular MG False-positive antiAChR antibody test results have been reported in patients with the following: Thymoma without MG LambertEaton myasthenic syndrome Small cell lung cancer Rheumatoid arthritis treated with penicillamine 13% of the population older than 70 years Other studies include: Plain chest radiographs may identify a thymoma as an anterior mediastinal mass Chest computed tomography is important to identify or rule out thymoma or thymic enlargement in all cases of MG In strictly ocular MG, magnetic resonance imaging of the brain and orbit is helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG Electrodiagnostic studies (repetitive nerve stimulation and single-fiber electromyography)

Common s/s of SLE

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE. Patients may present with any of the following manifestations: Constitutional (eg, fatigue, fever, arthralgia, weight changes) Musculoskeletal (eg, arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis) Dermatologic (eg, malar rash, photosensitivity, discoid lupus) Renal (eg, acute or chronic renal failure, acute nephritic disease) Neuropsychiatric (eg, seizure, psychosis) Pulmonary (eg, pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, interstitial lung disease) Gastrointestinal (eg, nausea, dyspepsia, abdominal pain) Cardiac (eg, pericarditis, myocarditis) Hematologic (eg, cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia)

Sjogren Syndrome--glandular pathology

The pathology of a typical involved salivary or lacrimal gland in Sjögren syndrome reveals aggregations of lymphocytes—periductal at first, then panlobular. These cells are primarily CD4 T cells (75%) and memory cells, with 10% B cells and immunoglobulin-secreting plasma cells. Extraglandular involvement in Sjögren syndrome manifests in part as hypergammaglobulinemia and the production of multiple autoantibodies, especially ANA and RF. This may be due to polyclonal Bcell activation, but the cause of this expanded activation is not known.

SLE--diagnostic criteria

The presence of 4 of the 11 American College of Rheumatology (ACR) criteria yields a sensitivity of 85% and a specificity of 95% for SLE. The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic: Serositis Oral ulcers Arthritis Photosensitivity Blood disorders Renal involvement Antinuclear antibodies Immunologic phenomena (eg, dsDNA; antiSmith [Sm] antibodies) Neurologic disorder Malar rash Discoid rash The following are useful standard laboratory studies when SLE is suspected: CBC with differential Serum creatinine Urinalysis with microscopy Other lab tests that may be used in the dx of SLE: ESR or CRP results Complement levels Liver function tests Creatine kinase assay Spot protein/spot creatinine ratio Autoantibody tests Imaging studies The following imaging studies may be used to evaluate patients with suspected SLE: Joint radiography Chest radiography and chest CT scanning Echocardiography Brain MRI/ MRA Cardiac MRI

Myasthenia Gravis Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles.

The presentation of MG has the following characteristics: The usual initial complaint is a specific muscle weakness rather than generalized weakness Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs during the course of illness in 90% The disease remains exclusively ocular in only 16% of patients Rarely, patients have generalized weakness without ocular muscle weakness Bulbar muscle weakness is also common, along with weakness of head extension and flexion Limb weakness may be more severe proximally than distally Isolated limb muscle weakness is the presenting symptom in fewer than 10% of patients Weakness is typically least severe in the morning and worsens as the day progresses Weakness is increased by exertion and alleviated by rest Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions. Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles. About 87% of patients have generalized disease within 13 months after onset. Less often, symptoms may remain limited to the extraocular and eyelid muscles for years. The following factors may trigger or worsen exacerbations: Bright sunlight Surgery Immunization Emotional stress Menstruation Intercurrent illness (eg, viral infection) Medication (eg, aminoglycosides, ciprofloxacin, chloroquine, procaine, lithium, phenytoin, betablockers, procainamide, statins)

What are IgE Receptor Complexes and what (2) features distinguish these antigen receptors from those on T and B lymphocytes?

The stable complexes of IgE and FcRI provide mast cells, basophils, and eosinophils with antigen-specific receptors 1. Effector function is immediate, does not require proliferation, differentiation. 2. Each cell can carry a range of IgE molecules and not just single antigen specific receptor.

Guillain-Barré syndrome (GBS) can be described as a collection of clinical syndromes that manifests as an acute inflammatory polyradiculoneuropathy with resultant weakness and diminished reflexes. Although the classic description of GBS is that of a demyelinating neuropathy with ascending weakness, many clinical variants have been well documented in the medical literature.

The typical patient with GBS, which in most cases will be acute inflammatory demyelinating polyradiculoneuropathy (AIDP), presents 2-4 weeks following a relatively benign respiratory or gastrointestinal illness with complaints of finger dysesthesias and proximal muscle weakness of the lower extremities. The weakness may progress over hours to days to involve the arms, truncal muscles, cranial nerves, and muscles of respiration. Common complaints associated with cranial nerve involvement in GBS include the following: Facial droop (may mimic Bell palsy) Diplopias Dysarthria Dysphagia Ophthalmoplegia Pupillary disturbances Most patients complain of paresthesias, numbness, or similar sensory changes. Paresthesias generally begin in the toes and fingertips, progressing upward but generally not extending beyond the wrists or ankles. Pain associated with GBS is most severe in the shoulder girdle, back, buttocks, and thighs and may occur with even the slightest movements. The pain is often described as aching or throbbing in nature.

Myasthenia Gravis--therapy/treatment

Therapy for MG includes the following: Anticholinesterase (AchE) inhibitors Immunomodulating agents Intravenous immune globulin (IVIg) Plasmapheresis Thymectomy

SLE--genetics

There is a clear genetic component in SLE, with a sibling risk ratio 8 fold to 29 fold higher than that in the general population and a 10 fold increase in disease concordance in identical twins. In addition, there is a 24-56% concordance rate in monozygotic twins, compared with a 25% risk in dizygotic twins

Describe MCTD

Tissue Fibrosis - constrictive cardiac disease - sudden death

What are the 4 types of Hypersensitivity and their effector mechanisms of the adaptive immune response

Type I - Immediate Hypersensitivity (IgE) Type II - Antibody-mediated Cytotoxicity (IgM, IgG) Type III - Immune-complex mediated (IgM, IgG) Type IV - Delayed Hypersensitivity (CD4, CD8 T cells)

Describe the Autoimmune pathology mediated in Myasthenia Gravis. What Type of Hypersensitivity is this?

Type II Hypersensitivity

Describe the Autoimmune pathology mediated in SLE. What type of Hypersensitivity is this?

Type III Hypersensitivity

Describe the Autoimmune patholgy mediated in Type I Diabetes. What Type of Hypersensitivity is this?

Type IV Hypersensitivity

Guillain-Barre Syndrome--respiratory complaints

Typical respiratory complaints in GBS include the following: Dyspnea on exertion Shortness of breath Difficulty swallowing Slurred speech Ventilatory failure with required respiratory support occurs in up to one third of patients at some time during the course of their disease.

Sjogren Syndrome--possible disease triggers

Viruses are viable candidates as environmental triggers, although proof of causation has remained elusive, and certainly no single virus has been implicated. Epstein Barr virus (EBV), HTLV1, human herpesvirus 6 (HHV6), HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) may have a role. Sjögrenlike syndromes are seen in patients infected with HIV, HTLV1, and hepatitis C.

Fibromyalgia--prevalence

Wolfe et al estimated that the prevalence of fibromyalgia in the US general population was 2% (3.5% in women and 0.5% in men). A study by Vincent et al using the 2010 ACR diagnostic criteria estimated the prevalence of fibromyalgia at 6.4% (7.7% in women and 4.9% in men). It is likely that this higher prevalence rate is a more accurate estimate.

Rheumatoid Arthritis--epidemiology

Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%, increasing with age and peaking between the ages of 35 and 50 years. First degree relatives of individuals with RA are at 2-3x higher risk for the disease Women are affected by RA approximately 3x more often than men

In regards to Immediate Hypersensitivity, define a Th2 cell and its role. What activates it?

aExposure to antigen in the presence of IL-4 polarizes naïve CD4 T-cells toward a Th2 response, resulting in further IL-4 production and B-cell production of IgE Initial sensitization is therefore favored by Th2 response and inhibited by conditions promoting Th1 response. Interactions of Th2 cells with mast cells, basophils, and activated eosinophils amplify the allergic response.