C1D4: amyloidosis and immunologic disorders I

Amyloidosis Overview

• Amyloidosis is a group of diseases involving extracellular deposition of fibrillary proteins.
• These conditions can stem from abnormal quantities of normal proteins or normal quantities of mutant proteins.
• The common characteristic is the presence of beta-pleated sheets as the basic structural unit.
• Clinical presentations vary, leading to different classifications.

Types of Amyloidosis

• Systemic amyloidosis affects multiple organs throughout the body.
• Localized amyloidosis affects a single organ, such as the brain, thyroid, heart, or pancreas.
• Diagnosis involves biopsy of the affected organ, or a fat pad biopsy for systemic involvement.
• Congo red staining is used, and under polarized light, amyloid deposits show apple-green birefringence.

Mechanisms of Protein Misfolding in Amyloidosis

• Normal proteins may be produced in excessive amounts, leading to misfolding of a small fraction.
• Mutant proteins, even in normal amounts, tend to misfold, leading to aggregation.
• Misfolded proteins resist degradation.
• They accumulate and form insoluble beta-pleated sheets, which then aggregate into extracellular amyloid fibrils.

Classification of Amyloidosis

• Primary Amyloidosis (AL amyloidosis) is associated with plasma cell dyscrasias such as multiple myeloma, involving overproduction of light chains.
• Secondary Amyloidosis (AA amyloidosis) results from chronic inflammatory conditions with elevated serum amyloid A.

Organ Involvement and Manifestations

• Kidneys: Nephrotic syndrome with proteinuria, hypoalbuminemia, and edema develops.
• Heart: Restrictive cardiomyopathy and a stiff myocardium are seen.
• GI tract: Malabsorption and hepatomegaly occur.
• Peripheral nerves: Neuropathy and autonomic dysfunction develop.

Localized Amyloidosis Examples

• Alzheimer's disease: Aβ plaques in the brain cause memory loss and neurodegeneration.
• Familial Amyloid Cardiomyopathy (ATTR amyloidosis): Mutant transthyretin (TTR) deposits in the heart, causing restrictive cardiomyopathy.
• Senile Cardiac Amyloidosis: Wild-type TTR deposits in the heart, affecting elderly individuals.
• Type 2 Diabetes Mellitus: Islet amyloid polypeptide (IAPP) deposits in pancreatic beta cells, leading to dysfunction.

Protein Structure and Amyloid Formation

• Primary Structure: Amino acid sequence
• Secondary Structure: Formation of alpha helices or beta-pleated sheets.
• Tertiary Structure: Folding upon itself, forming protofibrils.
• Quaternary Structure: Aggregation into amyloid fibrils.

Gross Morphology of Amyloid Deposits

• Amyloid deposits appear as waxy, starchy, and pale material within affected organs.
• This can cause organ enlargement and dysfunction, such as cardiac thickening and renal enlargement.

AL Amyloidosis (Primary Amyloidosis)

• Kappa and lambda light chains are produced due to abnormal plasma cells, leading to amyloid deposits.
• Clinical Associations: The common underlying condition is multiple myeloma
• Other conditions include B-cell lymphomas (CLL/SLL).
• Organs commonly affected include the kidneys, heart, and nerves, leading to nephrotic syndrome, restrictive cardiomyopathy, and peripheral neuropathy.

AA Amyloidosis (Secondary Amyloidosis)

• Serum amyloid A protein is produced in response to chronic inflammation, resulting in amyloid deposits.
• Common Chronic Inflammation Causes: rheumatoid arthritis, cystic fibrosis, cancer or inflammatory bowel disease.
• Organs commonly affected include the kidneys, spleen, liver and gastrointestinal system.

Senile Cerebral Amyloidosis (Alzheimer’s Disease)

• Amyloid beta (Aβ) plaques accumulate in the brain, leading to cognitive decline and dementia.
• Clinical Impact: Can lead to Alzheimer’s disease, the most common cause of dementia, and Down syndrome through early-onset Alzheimer’s.

Cardiac Amyloidosis

• Atrial natriuretic peptide (ANP) and aging contribute to amyloid deposits in the heart.
• Clinical Impact: Results in restrictive cardiomyopathy and atrial fibrillation.

Endocrine Amyloidosis

• Procalcitonin deposition occurs in endocrine organs, particularly in medullary thyroid carcinoma (MTC).
• Clinical Impact: Aids in the diagnosis of MTC through elevated calcitonin levels and amyloid deposits on biopsy.

Sjögren’s Syndrome Overview

• Sjögren’s Syndrome: An autoimmune disorder affecting exocrine glands (e.g., salivary and lacrimal).
• Etiology is unknown , a genetic predisposition involving MHC haplotypes.
• MHC class II molecules present self-antigens to CD4+ T-helper cells.
• Environmental factors: viral infections, molecular mimicry or hormonal factors.

Sjögren’s Syndrome Epidemiology

• 0.5%–1% of the population affected.
• Half of rheumatoid arthritis patients are diagnosed with Sjögren’s syndrome.
• Can occur at any age but typically presents after 25 years.
• Most common in women in middle age.

Pathogenesis of Sjögren’s Syndrome

• Characteristic Lesion: Focal Lymphocytic Sialadenitis (FLS) occurs
• Leads to infiltration, autoantibodies and diminished tear production
• Dysfunction can cause skin dryness, tracheal irritation or vasculitis.

Immune Mechanism in Sjögren’s Syndrome

• Dysfunctional systems in exocrine glands
• In Sjögren’s syndrome, T cells react inappropriately, activating B cells to produce anti-nuclear antibodies (ANAs), including Anti-SSA (Ro) or Anti-SSB (La).
• Classification Types: Primary Sjögren’s syndrome (Sicca syndrome) occurs alone or secondary.

Clinical Presentation of Sjögren’s Syndrome

• Symptoms include dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia) and respiratory issues
• Other dryness issues may include swollen glands or increased risk of infections.

Diagnosing Sjögren’s Syndrome

• Tests measure secretion
• Blood tests: presence of certain antibodies
• Lip biopsy.

DiGeorge Syndrome Overview

• Overview: A genetic condition caused by a deletion on chromosome 22q11.2
• This microdeletion was first identified by Dr. Antle de George in 1965.
• Most cases of DiGeorge syndrome arise de novo (i.e., newly in an individual) and are not inherited from a parent.
• Common Features: thymus/ parathyroid Hypoplasia, cardiac abnormalities and T-cell Dysfunction

Genetics of DiGeorge Syndrome

• Key Genes Involved: The TBX1 Gene encodes a transcription factor important in pharyngeal pouches development.
• Lack of TBX1 results in thymic hypoplasia (underdeveloped thymus), leading to a deficiency in the maturation of T-cells, which are essential for proper immune function.

Clinical Features of DiGeorge Syndrome

• Immunologic Impact: T-cell Deficiency, caused by thymic hypoplasia
• There are also partial and complete syndrome types.
• Parathyroid Impact: Hypocalcemia is caused due to a lack of PTH release.
• Cardiac Abnormalities: Tetralogy of Fallot & Truncus arteriosus

Other Common Manifestations

• Craniofacial Features: may include Cleft palate of distinct facial features
• Behavioral and Psychiatric Issues: High risk of psychiatric disorders such as schizophrenia or ADHD.

Managing and Treating DeGeorge Syndrome

• Immune Deficiency: Treated with infections or, in severe cases (complete DiGeorge syndrome), the thymus is repaired with transplantation
• Hypocalcemia Management: supplements and vitamin D.
• Cardiac Defects: Surgical repair restores function
• Psychiatric Care: Therapy or medicine.

Systemic Lupus Erythematosus (SLE) Introduction

• SLE is a chronic autoimmune disease affecting multiple organs and tissues.
• It is considered the disease due to its broad impact and changing symptoms over time.
• The disease is complex with multiple factors.
• Multifactorial with impaired clearance, inflammation etc.

Epidemiology of SLE

• Worldwide Prevalence: Predominant in women.
• Primarily affects women aged 15-44 years.
• Ethnic Groups: More prevalent in individuals of African descent, American Indians, and Alaska Natives.

Pathogenesis of SLE

• Genetic predisposition, such as certain HLA genes.
• Environmental triggers, such as UV radiation, infections.
• Immune and inflammatory stimuli cause a defective immune response.

SLE Immune Response

• Extracellular neutrophil traps (NETs) exacerbate inflammation in SLE.
• T cell dysregulation shifts to Th17 or double-negative cells.
• Genes Involved: HLA, BLK, STAP.

Mechanisms of Disease Development in SLE

• T cell Dysfunction: T cells have defective differentiation and activation.
• Apoptosis and Immune Complex Formation: UV-exposed skin cells release autoantigens, which can form dangerous immune complexes
• A classic symptom is the butterfly rash.

Environmental and Genetic Triggers of SLE

• Cigarette Smoking: An environmental risk factor that contributes to the development and exacerbation of SLE, likely through its effect on immune system modulation.
• Infections- Epstein-Barr Virus (EBV) has been shown to trigger the immune system in genetically predisposed individuals, potentially leading to the development of lupus.
• Medications: Certain medications, including hydralazine and isoniazid, can induce drug-induced lupus, a form of lupus triggered by drug exposure.
• Sex Hormones: Estrogen is thought to contribute to the higher incidence of lupus in women

Omen Syndrome Overview

• Omen syndrome is a severe combined immunodeficiency (SCID)
• It is a rare genetic disorder where the immune system does not function properly, leaving affected individuals highly susceptible to infections.
• SCID often leads to severe, life-threatening infections.

Epidemiology of Omen Syndrome

• First characterized in 1965, but recognized prevalence remains unknown
• Incidence pattern: Omen syndrome is inherited in an autosomal recessive pattern.
• Both parents are typically carriers of the mutation and usually asymptomatic (they don't show symptoms of the disease but can pass on the mutation to their children).

Pathogenesis of Omen Syndrome

• Mutations in RAG1 and RAG2: These genes are critical in the process known as V(D)J recombination to form adaptive immunity which is diminished.
• Leaky recombination: Due to the mutations in RAG1 and RAG2, there is incomplete or "leaky" recombination of the T and B cell receptors.
• Development of autoimmunity: The defective immune system may recognize the body’s own cells and tissues as foreign, triggering autoimmune reactions that damage organs and tissues.

Clinical Presentation of Omen Syndrome

• Age of onset: Typically presents in the first year
• Hallmarks: Severe Immune Deficiencies and Infections.
• Other Symptoms: Erythroderma (Red, Inflamed Skin Rash), Alopecia (Hair Loss) and Lymphadenopathy (Enlarged Lymph Nodes).

Immunologic Mechanisms of Omen Syndrome

• T cell malfunction, caused by defective adaptive immunity.
• B cell deficiency leads to failure to mount a natural immune response.
• Genetic Mutations: RAG1 and RAG2 mutations, which impair VDJ recombination.