Serology Exam #2: Lecture #8

Autoimmunity & Immunodeficiency

Define: Autoantibodies

T-cell-mediated immune responses directed against host antigen

Central tolerance

• the destruction of potentially self-reactive lymphocytes

• Occurs in the primary lymphoid organs

• T cells mature and encounter self-antigens

• Any T cells that show affinity towards self are eliminated

Peripheral Tolerance

• lymphocytes that recognize self-antigen in secondary lymphoid organs are rendered incapable of reacting with those antigens

• Maintains functional balance between Th1 and Th2 lymphocytes

• Tregs play a role in this process

Systemic Lupus Erythematosus (SLE): Pathogenesis, patients develop, complexes, strong association

• A chronic systemic inflammatory disease that affects multiple organ systems (skin, kidneys, joints, heart, lungs, brain, blood vessels)

• Patients develop numerous autoantibodies

• Immune complexes form, triggering C’ activation, chemotaxis of neutrophils, & inflammation

• Strong association with specific HLA-DR or HLA-DQ genes

Testing for SLE: Test, antibodies direct against, antibodies (5)

• Antinuclear antibodies (ANA) test

• Directed against antigens in cell nuclei

• Includes:

  • Anti-ds DNA (lupus-specific)

  • Anti-ss DNA

  • Anti-histones and nucleosomes

  • Antibodies to centromere or nucleolar components

  • Anti-ENA (anti-Sm specific for SLE, anti-RNP, anti- SS-A, anti-SS-B)

Phospholipid Antibodies: Associated with, increased risk, can cause, prolonged

• Associated with deep vein and arterial thrombosis

• Increased risk of recurrent pregnancy loss

• Can cause false-positive results in nontreponemal tests for syphilis

• Prolonged APTT and PT times

Rheumatoid Arthritis (RA): Pathogenesis, destroys, TNF, overly active cells, complexes

• Chronic arthritis of the peripheral joints that can progress to joint deformity and disability

• Inflammation destroys the bone and cartilage

• TNF-alpha plays a key role in the process

• Overly active osteoclasts absorb the bone

• Autoantibodies combine with antigens to form immune complexes.

Laboratory Testing for RA: RF & Anti-CCP

• Rheumatoid factor (RF): IgM autoantibody that reacts with Fc portion of IgG

• Anti-CCP: Autoantibody directed against cyclic citrullinated peptide (peptide containing a modified arginine); highly specific for RA

• ANAs, ESR, CRP, Complement assays

Granulomatosis with Polyangiitis (GPA): Pathogenesis, progresses, most patients have, neutrophil activation results

• Rare autoimmune disease involving inflammation of small- to medium-sized blood vessels and respiratory tract

• Progresses to more systemic disease involving other organs

• Most patients have antibodies to neutrophil cytoplasmic antigens (proteinase 3)

• Neutrophil activation results in damage to vascular endothelium and a Th1 response

Hashimoto’s Thyroiditis: Pathogenesis, symptoms, autoantibodies directed against

• Immune destruction of the thyroid gland produces hypothyroidism

• Symptoms include fatigue, dry skin, weight gain, brittle hair, formation goiter

• Autoantibodies directed against thyroglobulin (anti-thyroglobulin)

Hashimoto’s Thyroiditis: Lab results (TSH, T4, antibodies)

• Normal or high TSH

• Low Free T4

• Anti-TPO & Anti-Tg

Graves’ Disease

• An AITDS characterized by hyperthyroidism

• Symptoms: nervousness, weight loss, rapid heartbeat, goiter, exophthalmos

• TRAbs produced: Autoantibodies to thyroid-stimulating hormone (anti-TSHR)

Grave’s Disease: Laboratory Results (TSH, FT4, antibodies)

• low TSH

• high FT4

• antibodies to TPO & Tg

• Antibodies to THSR involves bioassays (tissue cell culture); expensive and difficult

Type I Diabetes Mellitus: Pathogenesis, autoantibodies against, long term effects

• Endocrine disorder characterized by hyperglycemia

• Autoantibodies destroy beta cells in pancreas → insulin deficiency

• Long-term effects: Cardiovascular disease, kidney dysfunction, nerve damage, blindness, infections

Type I Diabetes Mellitus: Lab Results (blood glucose, HbA1c, autoantibodies)

• Increased glucose blood level

• Elevated HbA1c

• Autoantibodies to: Glutamic acid decarboxylase (GAD), Insulinoma antigen 2 (IA-2), & Islet cell antibodies (ICA)

Celiac Disease: Pathogenesis, triggered by, symptoms

• Affects small intestine and other organs

• Triggered by gluten

• Symptoms: Diarrhea, abdominal pain and bloating, others

Celiac Disease: Autoantibodies (3)

• Autoantibodies form in HLA-DQ2 or HLA-DQ8- positive people to:

  • Gliadin (a component of gluten) and DGPs

  • Tissue transglutaminase (tTG) [IgA]

  • Endomysium (EMA)

Autoimmune hepatitis (AIH): Cells targeted & Antibodies (4)

• Hepatocytes targeted

• AIH-1- Positive for SMA, ANAs

• AIH-2- Positive for LKM-1 or LC-1 antibodies

Primary biliary cirrhosis (PBC): Pathogenesis & Antibody

• Destruction of intrahepatic bile ducts; cholestasis

• Majority of patients produce mitochondrial Abs (AMAs)

Multiple Sclerosis (MS): Pathology, antibodies, Pathogenesis

• autoimmune disorder involves inflammation and destruction of the CNS

• Most patients produce antibodies against myelin basic protein

• Plaques form in white matter of brain and spinal cord → destruction of myelin sheath of axons

Multiple Sclerosis (MS): Lab Findings

• Lesions seen on magnetic resonance imaging

• Increased immunoglobulins in spinal fluid and increased IgG index

• Oligoclonal bands on protein electrophoresis of CSF

Myasthenia Gravis: Pathogenesis & Antibodies

• Affects neuromuscular junction → weak skeletal muscles

• Most patients have antibodies to acetylcholine receptors

  • Block binding of ACH to its receptor and transmission of nerve impulses that activate muscles

• Anti-ACHR autoantibodies can be detected by RIA

Goodpasture’s Syndrome: Autoantibodies, complexes, antibodies

• Autoantibodies to basement membranes lining the renal glomeruli and lung alveoli

• Immune complexes bind to basement membranes: Attract complement & Type II hypersensitivity

• Antibodies to glomerular basement membranes (GBM) found in most patients

Goodpasture’s Syndrome:

• Indirect immunofluorescence or ELISA

• Tissue-bound anti-GBM detected by direct immunofluorescence on kidney biopsy sections

  • produces a smooth, linear, ribbon-like fluorescence along the GBM

Agammaglobulinemia: Category, decreased, transient hypogammagloblinemia

• category 3: Predominantly Antibody deficiencies (immunodeficiency)

• significantly decreased serum levels of immunoglobulins

• Transient hypogammaglobulinemia of infancy: Delayed development in Ig production (especially IgG)

Selective IgA deficiency: Low levels, symptoms

• Low IgA levels, perhaps because of impaired differentiation to IgA plasma cells

• Patients may be asymptomatic or more susceptible to infections, allergies, & autoimmunity

Severe Combined Immunodeficiency Disease (SCID): Category, cells affected, x-linked recessive form caused by

• Category 1; All effect T and B cell function

• All involve a defect in normal T-cell development

• May affect B-cell and NK-cell development, depending on type

• X-linked recessive form caused by IL2RG gene mutation

Purine-Nucleoside Phosphorylase (PNP) Deficiency: Pathogenesis, genetics, results in

• Affects enzymes involved in purine metabolism

• Rare, autosomal recessive; Presents in infancy

• Results in decreased number of T cells

Wiskott-Aldrich Syndrome: Genetics, defect in, defective function of, IgM, IgA, IgG, IgE

• Rare, X-linked recessive

• Defect in CD43: Integral membrane protein needed for signal transduction in lymphocytes

• Defective T-cell function

• Decreased IgM

• Normal IgA and IgG

• Increased IgE

DiGeorge Anomaly: Pathogenesis, genetics, results in (5)

• Developmental abnormality in third and fourth pharyngeal pouches in embryo

• Most patients have deletion in chromosome 22

• results in:

  • Underdevelopment of thymus and decreased T cells

  • Hypoparathyroidism and hypocalcemia

  • Cardiac abnormalities

  • Mental retardation

  • Abnormal facial features

Chronic Granulomatous Disease (CGD)

• Defect in NADPH oxidase

• Neutrophils unable to produce reactive forms of oxygen required to kill phagocytosed bacteria

Glucose-6-phosphate dehydrogenase deficiency: Inability to produce

• G6PD deficiency

• Inability to produce enough NADPH for respiratory burst

Myeloperoxidase Deficiency

• Primary neutrophil granules

• Recurrent yeast infections

Deficiencies in: Early complement components vs Late (associated with), C1 esterase inhibitor

• early: C2 most common; C3 deficiency associated with recurrent infections with encapsulated bacteria

• late: Associated with Neisseria infections

• C1: Causes hereditary neuroangioedema