Graft vs. Host Disease (GVHD)

Graft vs. Host Disease (GVHD)

• GVHD is a significant cause of morbidity and mortality following stem cell transplantation.
• GVHD occurs when the graft contains immune cells, the host is immunosuppressed, and the host is immunologically different from the donor.

Organs Affected by GVHD

• Skin involvement occurs in 70-74% of cases, often presenting as a pruritic or painful maculopapular rash, commonly affecting the palms, soles, and nape of the neck.
• Gastrointestinal (GI) tract involvement occurs in 44% of cases, leading to symptoms like diarrhea, nausea, and vomiting, potentially resulting in severe malabsorption and dehydration.
• Liver involvement features antigen-presenting cells interacting with donor T cells, which amplifies the immune response. Abnormal lab values include elevated bilirubin and alkaline phosphatase levels.

GVHD Mechanism

• Host dendritic cells present host antigens to donor helper T cells via MHC Class II molecules, activating them.
• Activated TH1 cells release cytokines like Interleukin-2 (IL-2), Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), IL-1, and IL-6, stimulating T cell proliferation, enhancing antigen presentation, and promoting inflammation.
• Cytotoxic T cells recognize host antigens on MHC Class I molecules, releasing perforin and granzymes that induce apoptosis in target cells.

Wiskott-Aldrich Syndrome

• Wiskott-Aldrich syndrome is a rare X-linked disorder primarily affecting males and results from mutations in the WAS gene (Xp11.23).
• This syndrome is underreported in some regions due to misdiagnosis.
• Mutations in the WAS gene disrupt cytoskeletal rearrangement, which impairs immune cell function and communication, critical for effective immunological synapse formation.

Clinical Presentation of Wiskott-Aldrich Syndrome

• The classic triad of symptoms includes immunodeficiency, thrombocytopenia, and eczema.
• Immunodeficiency results from impaired immune cell migration, adhesion, and T cell-B cell interaction, leading to T cell and B cell depletion.
• Thrombocytopenia causes easy bruising and prolonged bleeding times.
• Eczema presents as chronic skin inflammation due to a skewed Th2 response, resulting in high IgE levels.
• WAS patients have an imbalance between Th1 and Th2 cells, shifting towards a Th2-dominant response, leading to high IgE and allergic inflammation.
• B cell function is impaired, leading to low IgM levels and elevated IgE and IgA with IgG levels normal.

Myasthenia Gravis Epidemiology

• Myasthenia gravis is an autoimmune disease impacting all ethnic backgrounds, resulting from autoantibodies altering acetylcholine receptors (AChRs) at the neuromuscular junction.
• Young women under 40 and older men in their 60s and 70s most commonly affected, the first possible due to hormonal factors.
• Neonatal myasthenia gravis can occur if a fetus acquires anti-AChR antibodies from the mother.
• It does not run in families and is not inherited nor communicable.

Symptoms of Myasthenia Gravis

• Muscle weakness worsens with activity and improves with rest.
• Common symptoms include Diplopia (double vision) and Ptosis (drooping eyelids)
• Diplopia arises from weakened eye muscles, and ptosis results from weakened eyelid muscles.
• Bulbar muscle weakness → Difficulty swallowing or impaired speech.
• If respiratory muscles weaken, this can cause dyspnea
• Respiratory muscle weakness can lead to a life-threatening condition.

Pathophysiology of Myasthenia Gravis

• Type II hypersensitivity reaction drives the immune system damages its own tissues.
• Autoantibodies target nicotinic AChRs, preventing acetylcholine binding and initiating muscle contraction.
• Autoantibodies activate the complement system, leading to inflammation and muscle cell destruction.
• Muscle-specific receptor tyrosine kinase (MuSK) antibodies target intracellular proteins, leading to muscle cell destruction.
• Tumors can induce an immune response that results in the production of autoantibodies, referred to as paraneoplastic myasthenia gravis

Rheumatoid Arthritis Etiology and Epidemiology

• RA is a disease with unknown origin, more common in women between 30-50.
• Prevalence is higher in North America and Europe.
• HLA-DRB1 and HLA-DR4 alleles as primary genetic risk factors.
• RA is an autoimmune disease in which the body mistakenly attacks its own tissues, particularly the synovial membrane.

Rheumatoid Arthritis Pathogenesis

• T-helper cells activate B cells, producing autoantibodies.
• Macrophages and fibroblasts become activated, destroying cartilage and bone.
• Cytokines (TNF-alpha, IL-6 and IL-1) promote inflammation, joint swelling, pain, and destruction.
• Rheumatoid factor (RF, an IgM antibody targets IgG antibodies) and anti-citrullinated protein antibodies (ACPAs) damage joints and tissues.

Clinical Manifestations of RA

• Joints affected in symmetrical pattern (hands, knees, feet).
• Joint damage causes deformities: ulnar deviation, buttonhole deformity, swan-neck deformity, baker's cyst.
• Non-specific inflammation includes fever, fatigue, weight loss, and muscle weakness.
• Vasculitis increases risks of heart attack and stroke.
• Anemia of chronic disease.
• Lung involvement causes interstitial lung disease.
• Bone erosion causes increased bone resorption.
• Vasculitis causes vascular damage

Rheumatoid Arthritis Treatment

• Reduce inflammation, prevent joint damage, control symptoms, and maintain function.
• Treatment also includes: disease-modifying anti-rheumatic drugs (DMARDs), biologics targeting TNF-alpha or IL-6, and JAK inhibitors
• Corticosteroids help with acute flare-ups, but not for long-term due to side effects.
• Physical therapy to maintain joint function and flexibility.
• RA leads to long-term disability if not properly treated.
• RA is associated with increased mortality from cardiovascular disease.

Hashimoto’s Thyroiditis Etiology

• Hashimoto's thyroiditis cause is not fully understood but HLA-DR3 and HLA-DR5 and viruses are contributing factors.
• More common in women between 30-50 years old (middle aged).
• More common in patients with celiac disease, lupus, rheumatoid arthritis, Sjögren’s syndrome, or type 1 diabetes.

Hashimoto’s Thyroiditis Clinical manifestations

• Destruction causes an enlargement of the thyroid gland, which might create the appearance of a mass in the throat.
• Thyroid hormone production becomes erratic, causing fluctuating hormone levels eventually leading to Hypothyroid state .
• Causes fatigue, unexplained weight gain, cold intolerance, joint and muscle pain, dry skin, thinning hair, heavy or irregular menstrual periods, slowed heart rate.

Hashimoto's Thyroiditis Pathogenesis

• Primarily a cell-mediated autoimmune disease.
• Initial step is cytotoxic T cell (CD8+ cells)-mediated destruction of thyroid cells.
• Antibodies against thyroid peroxidase (TPO) and thyroglobulin are formed, helping confirm diagnosis.
• Progression includes complement system activation resulting in lysis (destruction).