Autoimmunity PDF

Autoimmunity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to understand: • Central and peripheral tolerance • Theories of autoimmunity • Autoimmune diseases Immune System Module Autoimmunity Autoi...

Autoimmunity Dana M. Tofiq MBChB, FAAAAI Assistant Professor of Allergy & Immunology Learning Objectives By the end of this session, students should be able to understand: • Central and peripheral tolerance • Theories of autoimmunity • Autoimmune diseases Immune System Module Autoimmunity Autoimmunity is a condition in which the body’s own immunologically competent cells or antibodies act against its self-antigens resulting in structural or functional damage. Paul Ehrlich had first introduced the concept of autoimmunity; he termed this condition as “horror autotoxicus”. Immune System Module Autoimmunity ❖ Normally immune system does not react to its own antigens i so due to a protective mechanism called tolerance. Any breach in tolerance mechanisms predisposes to several autoimmune diseases. ❖ Therefore, before going into the details on mechanisms of autoimmunity; it is essential to know about the various tolerance mechanisms that the human immune system possesses. Immune System Module Immunological tolerance is a state in which an individual Immunological Tolerance is incapable of developing an immune response against his own tissue antigens. It is mediated by two broad Mechanisms: central tolerance and peripheral tolerance. Immune System Module Central Tolerance E.FI This refers to the deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e. in the thymus for T cells and in the bone marrow for B cells). Immune System Module Central Tolerance 1. In thymus: During the T cell development in thymus, if any self-antigens are encountered, they are processed and presented by thymic antigen presenting cells (APCs) in association with self-MHC. Any developing T cell that expresses a receptor for such self-antigen is negatively selected (i.e. deleted by apoptosis). Therefore, the e I resulting peripheral T cell pool is devoid of self-reactive Cells. Immune System Module Central Tolerance 2. In bone marrow: When developing immature B cells in o a the bone marrow encounter a self-antigen during their development, the tolerance is developed by: Immune System Module Central Tolerance ❖ Receptor editing: It is a process by which B cells reactivate the machinery of antigen receptor gene rearrangement (mainly genes coding for light chains), so that a different (edited) B cell receptor will be produced which no longer recognizes the self-antigen. ❖ Negative selection: After receptor editing, if the B cells again recognize a self-antigen, then they are destroyed by subjecting them to apoptosis. Immune System Module Central Tolerance However, the process of central tolerance is not completely perfect. Many self-reactive T and B cells bearing receptors for self-antigens escape into the periphery. Hence, for counteracting those lymphocytes, peripheral tolerance takes a lead role. Immune System Module Peripheral Tolerance This refers to several back-up mechanisms that occur in the peripheral tissues to counteract the self-reactive T cells that escape central tolerance. It is provided by several mechanisms: 1. Ignorance: The self-reactive T cells might never encounter the self-antigen which they recognize and therefore remain in a state of ignorance. Immune System Module Peripheral Tolerance p 2. Anergy: It can be defined as unresponsiveness to antigenic It stimulus. The self-reactive T cells interact with the APCs presenting the self-antigen, but the costimulatory signal is blocked. The B7 molecules on APC bind to CTLA-4 molecules on T cells instead of CD28 molecules. Note: Normally, T cell activation requires two signals. Main signal (provided by antigen MHC complex of APC interacts with TCR on T cell) and a co-stimulatory signal (B7 molecules on APCs bind to CD28 on T cells). If selfantigens are processed and presented by APCs, that do not bear the co-stimulators, a negative signal is delivered, and the cell becomes anergic. Immune System Module Peripheral Tolerance 3. Phenotypic Skewing: Self-reactive T cells interacting with APCs presented with self antigens, undergo full activation, but might secrete nonpathogenic cytokines and chemokine receptors profile, hence although they are activated, fail to induce autoimmune response Immune System Module Peripheral Tolerance 4. Apoptosis by AICD: Self-reactive T cells e are activated after interacting with APCs presented with self-antigens. But the activation of T cells induces upregulation of Fas ligand which subsequently interacts with the death receptor Fas leading to apoptosis. This mechanism is called as activation-induced e cell death (AICD). Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas–FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens Immune System Module Peripheral Tolerance 5. Regulatory T cells (Treg cells): Treg cells can down regulate the self-reactive T cells through secreting certain cytokines (e.g. IL-10 and transforming growth factor β [TGF-β]) or killing by direct 0 a cell-to-cell contact. 6. Dendritic cells (DCs): When certain dendritic cells such as immature DCs and tolerogenic DCs capture the self-antigen for processing, they down regulate the expression of molecules of costimulatory ligands such as CD40 and B7 molecules or act indirectly by induction of regulatory T cells. Immune System Module Peripheral Tolerance separation 7. Sequestration of self-antigen: Certain self-antigens avoidrecognition by sequestration in can evade immune immunologically privileged sites, e.g. corneal proteins, testicular antigens and antigens from brain. Immune System Module Peripheral Tolerance t.s ❖ B cells can also exhibit peripheral tolerance. The self-reacting B cells that have escaped (10%) the central tolerance at bone marrow are further destroyed at spleen by several mechanisms such as downregulation of a B cell growth factor called B cell activating factor (BAFF). e Immune System Module Mechanisms of Peripheral Tolerance: A. Anergy; B. Phenotypic Skewing; C. Apoptosis Immune System Module Immune System Module Mechanisms of Autoimmunity Autoimmunity results due to breakdown of one or more of the mechanisms of immunological tolerance. 1. Breakdown of T Cell Anergy Normal cells that do not usually express costimulatory molecules (B7) can be induced to do so. Such induction may occur in presence of tissue necrosis and local inflammation. This mechanism has been postulated for: ❖ Multiple sclerosis ❖ Rheumatoid arthritis ❖ Psoriasis Effie chronic skin disease characterized by scaly red patches on the skin Immune System Module Mechanisms of Autoimmunity 2. Failure of AICD Failure of the autoreactive activated T cells to undergo activation-induced cell death (AICD), i.e. apoptosis via Fas-Fas ligand can lead to autoimmunity. It is observed in patients suffering from systemic lupus erythematosus (SLE). (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. 3. Loss of Treg Cells Autoimmunity can result following the loss of regulatory T cell-mediated suppression of self-reactive lymphocytes. Immune System Module 4. Providing T Cell help to Stimulate Self-reacting B Cells Antibody response to self-antigens occurs only when potentially self-reactive B cells receive help from T cells. For example, in autoimmune hemolytic anemia, administration of certain drugs may result in drug-induced alterations in the red cell surface that create antigens which can be recognized by helper T cells. Mechanisms of Autoimmunity Immune System Module T Cells Help to Stimulate Self-Reacting B Cells Immune System Module Mechanisms of Autoimmunity 5. Release of Sequestered Antigens The sequestered antigens are usually viewed as foreign to the immune system as they are never been exposed to the tolerance mechanisms during development of immune system. Injury to the organs leads to release of such sequestered antigens which are very well capable of mounting an immune response. Spermatozoa and ocular antigens released after trauma or surgery can cause post-vasectomy orchitis and post-traumatic uveitis. Immune System Module 6. Molecular Mimicry Mechanisms of Autoimmunity Some microorganisms share antigenic determinants (epitopes) with self-antigens, and an immune response against such microbes would produce antibodies that can cross react with self-antigen. aww ❖ For example, acute rheumatic fever results due to antibodies formed against streptococcal antigens (M protein), cross react with cardiac antigens (glycoproteins), due to antigenic cross reactivity. ❖ Molecular mimicry involving T cell epitopes: Examples include multiple sclerosis, where T cell clones reacting to myelin basic protein probably would have been induced by reacting against peptides derived from many microbes including viruses. Immune System Module Mechanisms of Autoimmunity 7. Polyclonal Lymphocyte Activation Several microorganisms and their products are capable of causing polyclonal (i.e. antigen-nonspecific) activation of T cells or B cells. ❖ Polyclonal T cell activation: Superantigens released from microbes (e.g. Staphylococcus aureus), polyclonally activate the T cells directly by binding to antigen nonspecific Vβ region of T cell receptors. ❖ Polyclonal B cell activation: It can be induced by products of various microbes such as Epstein-Barr virus, HIV, etc. Immune System Module Mechanisms of Autoimmunity 8. Exposure of Cryptic Self-epitopes Research has proved that “molecular sequestration” of antigens is much more common than anatomic sequestration. ❖ During development of immune system, not all epitopes of an antigen are effectively processed and presented to T cells. There are some non-dominant cryptic epitopes which remain sequestrated. Hence, T cell clones reacting against such epitopes are not deleted. ❖ Such cryptic self-epitopes can be released secondary to inflammation at a site of tissue injury, which can induce increased protease production and differential processing of released self-epitopes by APCs. Immune System Module Mechanisms of Autoimmunity 9. Epitope Spreading The self-peptides released due to persistent inflammation induce tissue damage (as occurs in chronic microbial infection) and are processed and presented by APCs along with microbial peptides. It is possible that, there may occur a shift or spread of T cell recognition to self-epitopes presented on APCs rather than recognizing microbial epitope. 10. Bystander Activation It is the nonspecific activation of bystander self-reactive TH1 cells. Activation of microorganism-specific TH1 cells leads to cytokine influx which causes an increased infiltration of various nonspecific T cells at the site of infection. Immune System Module Autoimmune Diseases Disease Autoimmune anemias Autoimmune hemolytic anemia Single Organ or Cell Type Autoimmune Diseases Self-antigen present on Type of immune response & Important features Auto-antibodies to RBC antigens triggers complement mediated lysis or antibody-mediated opsonization of the RBCs Drug induced Drugs alter the red cell membrane Drugs such as penicillin or methyldopa interact hemolytic anemia antigens with RBCs so that the cells become antigenic Pernicious anemia Intrinsic factor (a membrane-bound Auto-antibodies to intrinsic factor block the Pernicious anemia is a disease where not enough red protein on gastric parietal cells) uptake of vitamin B 12; leads to megaloblastic blood cells are produced due to a de ciency of vitamin B12. mostly people older affecting anemia Idiopathic Platelet membrane proteins Auto-antibodies against platelet membrane Thrombocytopenic (glycoproteins IIb-IIIa or Ib-IX) antigens leads to ↓platelet count Purpura is a blood disorder characterized by an abnormal decrease in the number of platelets in the blood. RBC membrane proteins Immune System Module Autoimmune Diseases Single Organ or Cell Type Autoimmune Diseases Disease Self-antigen present Type of immune response & Important features is a rare disorder in which your body mistakenly makes antibodies that attack the lungs and kidneys. on Goodpasture Renal and lung Auto-antibodies bind to basement-membrane antigens on kidney syndrome basement glomeruli and the alveoli of the lungs followed by complement is a rare autoimmune disease in which antibodies attack the basement membranes mediated injury leads to progressive kidney damage and pulmonary membrane in lungs and kidneys, leading to bleeding from the lungs, haemorrhage glomerulonephritis, and kidney failure. Myasthenia gravis Acetylcholine receptors Blocking type of auto-antibody directed against Ach receptors present on motor nerve endings, leads to progressive weakening of the skeletal muscles Graves’ disease Thyroid-stimulating hormone (TSH) receptor Anti-TSH auto-antibody (stimulates thyroid follicles, leads to hyperthyroid state) is a rare long-term condition that causes muscle weakness. It most commonly a ects the muscles that control the eyes and eyelids, facial expressions, chewing, swallowing and speaking. is an autoimmune disorder that leads to an overactive thyroid gland (hyperthyroidism). Immune System Module Autoimmune Diseases Disease Self-antigen present Type of immune response & Important features on Hashimoto’s thyroiditis Thyroid proteins and Auto-antibodies and TDTH cells targeted against thyroid antigen cells leads to suppression of thyroid gland. is an autoimmune disease in which the thyroid gland is gradually destroyed. ∙ Seen in middle aged females ∙ Hypothyroid state is produced (↓ production of thyroid hormones) Post-streptococcal Kidney Streptococcal antigen- antibody complexes are deposited on is a rare kidney disease that can develop after group A strep infections glomerulonephritis glomerular basement membrane Type 1 diabetes mellitus Beta cells present in TDTH cells and auto-antibodies directed against pancreatic beta is an autoimmune disease that originates islets of Langerhans cells cause ↓ production of insulin when cells that make insulin (beta cells) are destroyed by the immune system. of pancreas Immune System Module Autoimmune Diseases Disease Systemic lupus erythematosus Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Auto-antibodies are produced ∙ Age & sex - Women (20-40 years of age) are against various tissue antigens commonly affected; female to male ratio is such as DNA, nuclear protein, -10:1. RBC and platelet membranes. ∙ Immune complexes (self auto Ag-Ab) are formed; which are deposited in various organs ∙ Major symptoms - Fever, butterfly rash over the cheeks, arthritis, pleurisy, and kidney dysfunction Immune System Module Autoimmune Diseases Disease Rheumatoid arthritis Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Here, a group of auto-antibodies ∙ Age & sex - Women (40-60 years of age) affected against the host IgG antibodies ∙ Auto-antibodies bind to circulating IgG, forming are produced called RA factor. It IgM-IgG complexes that are deposited in the is an IgM antibody directed joints and can activate the complement cascade. against the Fc region of IgG. ∙ Major symptoms ACPA (Anti citrullinated peptide Main feature - Arthritis (chronic inflammation of the antibodies) are also produced joints, begins at synovium; most common joints involved are- small joints of the hands, feet and cervical spine) Other features - hematologic, cardiovascular, and respiratory systems are also frequently affected Immune System Module Autoimmune Diseases Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Disease Self-antigen present on Type of immune response & Important features Sjögren syndrome Ribonucleoprotein (RNP) antigens SS-A (Ro) and SS-B (La) present on salivary gland, lacrimal gland, liver, kidney, thyroid Auto-antibodies to the RNP antigens SS-A (Ro) and SS-B (La); leads to immune-mediated destruction of the lacrimal and salivary glands resulting in dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) Immune System Module Autoimmune Diseases Disease Scleroderma (Systemic Sclerosis) Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Nuclear antigens such as DNA Helper T cell (mainly) and auto-antibody mediated. topoisomerase and centromere Excessive fibrosis of the skin, throughout the body present in heart, lungs, GIT, Two typeskidney, etc 1.Diffuse scleroderma- Auto-antibodies against DNA topoisomerase I (anti-Scl 70) is elevated 2.Limited scleroderma- ↑Anticentromere antibody, characterized by CREST syndrome-calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia Immune System Module Autoimmune Diseases Disease Seronegative Spondyloarthropathies Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Sacroiliac joints & other Common characteristics- They present as rheumatoid vertebrae arthritis like features, but differ from it bySeveral types∙ Association with HLA-B27 ∙ Ankylosing spondylitis ∙ Pathologic changes begin in the ligamentous ∙ Reiter Syndrome attachments to the bone rather than in the ∙ Psoriatic Arthritis synovium ∙ Spondylitis With ∙ Involvement of the sacroiliac joints, and/or Inflammatory Bowel Disease arthritis in other peripheral joints ∙ Reactive arthritis ∙ Absence of RFs (hence the name "seronegative") ∙ Auto-Ab and immune complex mediated Immune System Module Autoimmune Diseases Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Disease Self-antigen present on Type of immune response & Important features Multiple sclerosis Brain (white matter) Self-reactive T cells produce characteristic inflammatory lesions in brain that destroys the myelin sheath of nerve fibers; leads to numerous neurologic dysfunctions Immune System Module Laboratory Diagnosis of Autoimmune Diseases Autoimmune diseases Autoimmune hemolytic anemias Goodpasture syndrome Laboratory diagnosis oCoombs test - red cells are incubated with an anti–human IgG antiserum IgG auto-antibodies are present on the red cells, the cells are agglutinated by the antiserum Biopsies from patients are stained with fluorescent-labeled anti-IgG and anti-C3b reveal linear deposits of IgG and C3b along the basement membranes. Immune System Module Laboratory Diagnosis of Autoimmune Diseases Autoimmune diseases Laboratory diagnosis SLE (Systemic lupus erythematosus) Detection of autoantibodies by indirect immunofluorescence assay (most widely used) and ELISA based techniques. • ANA (antinuclear antibody)- Positive in >90% cases (screening test). • Anti-double stranded DNA (dsDNA)-Highly specific (confirmation). • Anti-Sm antibodies Lupus band test- Direct immunofluorescence test - detect deposits of immunoglobulins and complement proteins in the patient's skin. LE cell test- No longer used because the LE cells are only found in 50–75% of SLE cases. Immune System Module Laboratory Diagnosis of Autoimmune Diseases Autoimmune diseases Laboratory diagnosis Scleroderma Anti-Scl 70 antibody is raised, detected by indirect immunofluorescence assay Sjögren’s syndrome Detection of SS-A (or anti-Ro) and SS-B (or anti-La) antibodies by indirect immunofluorescence assay. Immune System Module Laboratory Diagnosis of Autoimmune Diseases Autoimmune diseases Laboratory diagnosis Rheumatoid arthritis Rheumatoid factor (RF) (by latex agglutination test)- RF is an IgM autoantibody directed against Fc portion of IgG, good sensitivity. False positive - seen in other autoimmune diseases. ACPA (Anti-citrullinated peptide antibodies) is an auto-antibody to citrullinated peptides and proteins. It is positive only in 67% of cases; but is highly specific. Rose-Waaler test to detect RF is of historical importance, no longer used now. Immune System Module MS Learning Objectives By the end of this session, students should be able to: 1. Infer the importance of the process of negative selection in the prevention of autoimmune diseases. 2. Summarize the process of autoimmunity in rheumatoid arthritis. 3. Interpret the serological tests of SLE. 4. Extract the role of molecular mimicry in Guillain-Barré syndrome. Case Study 1: Ip L A 33 year-old female is being followed by her neurologist for her multiple tinwareremitting getbettersubtype after sclerosis. She was initially diagnosed with relapsing an episode of visual disturbance and an episode of paralysis. In her study of autoimmune diseases she encounters the topic of lymphocyte development and comes across a question which she poses to her neurologist during a routine follow-up visit: During the process of Tlymphocyte maturation, T cell receptors of many lymphocytes demonstrate a very high-affinity interaction with MHC molecules expressed on thymic medullary epithelial and dendritic cells. What process do these lymphocytes undergo at this time? A. Affinity maturation B. lsotype switching inthymus C. Negative selection in medulla D. Positive selection in cortex E. TCR DNA rearrangement Tiedreceptor is a degenerative disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Answer: C. Negative selection T-lymphocytes, or thymocytes, are initially produced in the bone marrow, but they migrate from that location to mature during the first trimester of gestation in the thymus. In the thymus, the processes of T-cell receptor (TCR) gene rearrangement, positive selection, negative selection, and express ion of extracellular membrane markers and co-stimulatory molecules occurs. Pro-T cells arrive at the thymus as "double negative" cells- indicating that they lack both CD4 and CD8 antigens and begin their differentiation in the subcapsular zone. Next, the process of TCR beta gene rearrangement occurs with simultaneous express ion of both CD4 and CD8. Once in thymic cortex, the alpha genes rearrange to produce a functional alpha-beta TCR. Subsequently, the processes of positive and negative selection occur with cells that fail either of these tests being eliminated by apoptosis. pregok Positive selection is the process by which only T cells expressing a TCR that is able to bind self MHC are allowed to survive. Those cells expressing a TCR that is not specific for self MHC are signaled for elimination by apoptosis. This process occurs after TCR DNA rearrangement and prior to the process of negative selection. It occurs in the thymic cortex and involves interaction of T cells with thymic cortical epithelial cells expressing self MHC. Positive selection is responsible for development of a T cell repertoire that can recognize self. Negative selection occurs after positive selection and is the process by which T cells possessing TCRs that bind with high affinity to selfantigen or self MHC class I or II are eliminated by apoptosis. Negative selection occurs in the thymic medulla and involves interaction of the developing T cells with thymic medullary epithelial and dendritic cells. This process serves to eliminate T cells that may be overly autoreactive against self-antigens and therefore may play a role in autoimmunity if not destroyed. This results in a population of T cells that have only an appropriately low affinity for self MHC molecules. Educational Objective: The process of negative selection in T cell maturation is essential for eliminating T cells that bind to self EE MHC or self-antigens with overly high affinity. This process occurs in the thymic medulla. If these cells were permitted to survive, they would likely induce immune and inflammatory reactions against self-antigens leading to autoimmune disease. Case Study 2: A 45-year-old woman comes to the office due to a long history of joint pain, swelling, and stiffness. She recently immigrated and had little access to medical care in her original country. On physical examination, her proximal interphalangeal and metacarpophalangeal joints are tender and swollen bilaterally, and her fingers appear significantly deformed. Subcutaneous nodules are palpated near the elbow. Laboratory studies are obtained to confirm the diagnosis. This patient's serum is most likely to contain lgM antibodies against which of the following substances? shunted factor A. Centromeres This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. B. Double-stranded DNA C. Fc portion of human lgG D. Mitochondrial extract E. Nuclear basic proteins F. Phospholipids G. Sheep erythrocytes Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily a ects joints. It typically results in warm, swollen, and painful joints. Pain and sti ness often worsen following rest Answer: C. Fc portion of human lgG Bilateral pain, stiffness, and deformity of the proximal interphalangeal and metacarpophalangeal joints are typical of advanced rheumatoid arthritis (RA). Morning stiffness, tenderness, and edema of the affected joints lowbonedensity predominate early in this disease. Later, osteopenia, erosions, and joint space narrowing lead to decreased range of motion and deformities (e.g., swan neck, ulnar deviation). Patients can also develop rheumatoid nodules, firm, non-tender, subcutaneous nodules that occur at pressure points such as the elbows or forearms. RA is due to failure of immune tolerance, with development of an autoreactive immune response directed against joint components (eg, type II collagen, citrullinated vimentin). CD4+ T-helper cells become activated by these self-antigens and release cytokines that promote chronic inflammatory synovitis. CD4+ T cells also induce B cells to synthesize rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). Rheumatoid factor is an antibody (typically lgM) specific for the Fc component of lgG. Rheumatoid factor binds circulating lgG and ACPAs bind modified self-proteins, forming immune complexes that depos it on the synovium and cartilage. These complexes activate complement in those locations, contributing to chronic inflammation and joint destruction. Educational Objective: Rheumatoid arthritis results from an immune response directed against autoantigens in the joints. Infiltrating CD4+ T cells secrete cytokines that promote inflammatory synovitis. They also stimulate B cells to produce See rheumatoid factor (lgM antibody specific for Fc component of lgG) and anticitrullinated protein antibodies that contribute to chronic inflammation and joint destruction. Oo 000 o Case Study 3: A 23-year-old woman comes to the office due to sharp, right-sided chest pain, fatigue, and fever for the past week. The chest pain is worsened with deep breathing. She has had no associated expectoration or shortness of breath. For the past 6 months, the patient also has had intermittent joint pains, predominantly in the knees and hands. She is sexually active with one male partner and uses an intrauterine device for contraception. Temperature is 38.3 C (100.9 F), blood pressure is 120/70 mm Hg, pulse is 89/min, and respirations are 18/min. BMI is 24 kg/m2. Examination shows mild erythema over the cheeks and a scratching sound over the right lower lung with breathing. Heart sounds are normal. There is no joint swelling. sotheremisnot Which of the following tests is most useful in confirming the diagnosis? A. Anti-double-stranded DNA antibodies B. Antistreptolysin O titers C. Nucleic acid amplification test of cervical swab D. Rheumatoid factor assay E. Serologic test for syphilis Answer: A. Anti-double-stranded DNA antibodies This young patient has pleuritis (chest pain worse with breathing, pleural rub), arthralgias, fever, and an erythematous rash on the cheeks. This presentation is concerning for systemic lupus erythematosus (SLE), a chronic inflammatory disease characterized by autoantibodies that bind self-antigens. Particular autoantibodies that are useful in the diagnosis of SLE include: 1. Antinuclear antibodies are found in virtually all patients with SLE but also in many other autoimmune disorders (i.e., high sensitivity, low specificity). f 2. Anti-double-stranded DNA antibodies are highly specific for SLE, but only approximately 60% of patients have high titers (i.e., low sensitivity, high specificity). 3. Anti-Smith antibodies (i.e., antibodies against small nuclear ribonucleoproteins) are present in 20%-30% of patients but are also highly specific. Common laboratory abnormalities include low C3 and C4 levels (due to activation of complement) and elevated inflammatory markers (e.g., Creactive protein, erythrocyte sedimentation rate). Hematologic abnormalities can include anemia, leukopenia, and thrombocytopenia, which occur due to chronic inflammatory effects on bone marrow and autoimmune hemolysis. Renal involvement can result in elevated serum creatinine, proteinuria, hematuria, or red cell casts visible on urinalysis. (Choice B) Antibodies to streptolysin O indicate recent streptococcal infection and are useful in the diagnosis of certain immune sequelae (e.g., glomerulonephritis, rheumatic fever). This patient has arthralgias, but no other major features of rheumatic fever (i.e., carditis, subcutaneous nodules, erythema marginatum, Sydenham chorea). (Choice C) Acute cervicitis is a common cause of fever in young, sexually active women. Evaluation commonly includes nucleic acid amplification testing (NAAT) for organisms such as gonorrhea, chlamydia, and trichomoniasis. Although disseminated gonorrhea can cause arthralgias and rash, pleuritis is not typical. (Choice D) Rheumatoid factor is an IgM antibody directed against the Fc portion of human IgG. It is classically associated with rheumatoid arthritis, although it may also be seen in other autoimmune diseases (including SLE) and is nonspecific. Rheumatoid arthritis can cause arthralgias and lung involvement, but rash is unexpected and joint swelling is usually prominent. (Choice E) Non-treponemal serologic tests (e.g., RPR, VDRL) are frequently used to screen for syphilis. Although secondary syphilis can manifest with synovitis and rash, it typically involves the palms and soles and pleural involvement is rare. Educational Objective: Antinuclear antibodies are found in almost all patients with systemic lupus erythematosus but are also found in many other autoimmune disorders Fatestranded DNA antibodies and antiand have low specificity. Anti-doubleSmith antibodies have lower sensitivity but higher specificity. a Case Study 4 A 32-year-old man is brought to the emergency department due to weakness and tingling that started in his feet and is now at his knees. A week ago, the patient noticed that his legs felt weak while climbing stairs. Since then, the weakness has progressively worsened every day. Today, he fell twice when attempting to walk. Medical history is insignificant, except for a mild respiratory infection 2 weeks ago that resolved spontaneously. The patient does not use tobacco, alcohol, or illicit drugs. He takes no medications. Vital signs are within normal limits. Physical examination shows marked weakness in the distal muscles and moderate weakness in the proximal muscles in both legs. Deep tendon reflexes are absent at the knees. This patient's condition is most likely associated with which of the following? A. Endomysial inflammatory infiltration B. Endoneurial arteriole hyalinization C. Endoneurial inflammatory infiltration D. Mutations of a muscle structural protein gene E. Toxin penetration through the blood-nerve barrier Answer: This patient has ascending symmetric weakness following a febrile illness, nerveusually afterinfection.itscommonin likely due to Guillain-Barré syndrome (GBS). GBS is an acute, immunemediated, demyelinating polyneuropathy thought to be due to molecular mimicry; infectious antigens provoke an immune response that cross-reacts with the myelin of the spinal roots and peripheral nerves, resulting in demyelination of peripheral nerves. Patients develop a symmetric, ascending flaccid paralysis and areflexia leading to eventual respiratory failure; cranial nerve involvement can also occur. This is typically preceded by an upper respiratory viral illness or an episode of diarrhea (due to Campylobacter jejuni). Inguinal Histology demonstrates an inflammatory infiltrate located within the endoneurium (the innermost layer of connective tissue that surrounds a nerve axon and its corresponding blood vessel). The infiltrate, consisting largely of lymphocytes and macrophages, extends from the small vessels (perivenular) to the associated nerve axon. Macrophages strip the myelin sheath from the axon, and lipid laden macrophages are seen following the engulfment of myelin. (Choice A) Endomysial inflammatory infiltration is characteristic of polymyositis (an immune-mediated inflammatory myopathy). Patients develop symmetric weakness; however, weakness is greater proximally than distally. (Choice B) Hyalinization of the nerve arterioles leads to ischemic nerve injury and is a cause of diabetic neuropathy. However, this occurs over an extended time (decades) in patients with long-standing, uncontrolled diabetes. (Choice D) Mutations in the gene that codes for the muscle protein dystrophin can cause either a complete absence of this protein (Duchenne muscular dystrophy) or its decreased synthesis (Becker muscular dystrophy). Both of these diseases cause progressive weakness and lead to Hotel (Choice D) Mutations in the gene that codes for the muscle protein dystrophin can cause either a complete absence of this protein (Duchenne muscular dystrophy) or its decreased synthesis (Becker muscular dystrophy). Both of these diseases cause progressive weakness and lead to eventual respiratory failure but weakness is worse proximally and patients present in early childhood with a waddling gait and calf enlargement. (Choice E) Corynebacterium diphtheriae can cause neuropathies due to Diphtheria toxin penetration through the blood-nerve barrier; however, diphtheria usually presents as pharyngitis with pseudomembrane formation and stridor. In addition, the neuropathy typically affects the cranial nerves prior to the peripheral nerves. Educational objective: Guillain-Barré syndrome is an acute demyelinating polyneuropathy. It is thought to be due to molecular mimicry and is commonly preceded by an upper respiratory viral illness or gastroenteritis. Segmental demyelination 0 of the peripheral nerves and an endoneural inflammatory infiltrate are seen on light microscopy.