C1D5: immunologic disorders I

Graft Versus Host Disease (GVHD) Overview

• GVHD is a systemic disorder where immune cells from a graft attack the recipient's body cells because they recognize the host as foreign.
• Immunologically competent cells are transplanted into immunodeficient recipients for GVHD to occur.

Settings for GVHD Occurrence

• Following bone marrow transplantation and related stem cell transplants, which is the most common scenario.
• Transplanting solid organs rich in lymphoid cells like the liver.
• After receiving a transfusion of unirradiated blood.

Epidemiology of GVHD

• Acute GVHD occurs in up to 50% of stem cell transplant recipients from an HLA-matched sibling donor.
• More than 10% of stem cell transplant recipients die from GVHD-related complications.
• HLA matching is critical to reduce GVHD risk, which increases significantly when donors and recipients are not well-matched.

Organs Typically Affected by GVHD

• Skin, with involvement in 70-74% of cases due to rapid skin cell division, making them a target for donor T cells. A pruritic or painful maculopapular rash often involves the palms, soles, and nape of the neck.
• Gastrointestinal (GI) tract, involved in 44% of cases due to the high turnover rate of epithelial cells in the gut. Symptoms include diarrhea, nausea, and vomiting, leading to severe malabsorption and dehydration.
• Liver, as antigen-presenting cells interact with donor T cells, amplifying the immune response. Elevated bilirubin and alkaline phosphatase levels indicate liver involvement, which can progress to hepatic failure.

Pathogenesis of GVHD

• Donor T cells recognize recipient cells as foreign and attack epithelial cells in the skin, liver, and gut, leading to acute GVHD.

Transplant Terminology

• Graft: Transplanted or donated tissue (e.g., bone marrow, peripheral blood, liver).
• Host: The person receiving the transplant.

Immune System Basics

• The immune system recognizes and attacks foreign invaders while leaving self-cells unharmed.
• Major histocompatibility complex (MHC) proteins, also known as human leukocyte antigens (HLA), distinguish self from non-self.

MHC and GVHD Risk

• MHC Class I molecules are on all nucleated cells.
• MHC Class II molecules are on antigen-presenting cells (APCs) like monocytes, macrophages, dendritic cells, and B cells.
• Each person has unique MHC genes, making HLA matching challenging.
• Minor histocompatibility antigens can trigger an immune response, even in HLA-identical individuals, leading to GVHD.

Key Elements Required for GVHD

• The graft must contain immune cells, mainly T cells, such as hematopoietic stem cells originating from bone marrow, peripheral blood, or umbilical cord blood.
• Host immune system must be suppressed to allow the donor’s immune cells enough time to proliferate and attack tissues.
• The host must be immunologically different from the donor, so the recipient’s HLA antigens appear foreign to the grafted immune cells, triggering an immune response.

GVHD Mechanism

• Host dendritic cells travel to lymph nodes and present host antigens to donor helper T cells via MHC Class II molecules, activating the donor helper T cells.
• Activated TH1 cells release cytokines including Interleukin-2 (IL-2), which stimulates T cell proliferation, and Interferon-gamma (IFN-γ), which enhances antigen presentation and macrophage activation.
• Cytotoxic T cells recognize host antigens on MHC Class I molecules and become activated, releasing perforin and granzymes. Perforin creates pores in target cells and granzymes enter through the pores to trigger apoptosis.
• Fas-FasL signaling also triggers apoptosis.

Final Outcome of GVHD

• Extensive tissue damage occurs in affected organs, such as skin, liver, and gut.
• Severe inflammation and immune-mediated destruction of host cells is caused.

Key Concept: Perfect HLA Matching vs. Minor Histocompatibility Antigens

• Perfect HLA matching means the donor's and recipient's HLA antigens are identical, which lowers the chance of the donor’s immune system attacking the recipient’s body.
• Minor histocompatibility antigens are small genetic differences between the donor and recipient, even in perfect HLA-matched transplants.
• In perfect HLA matches, the donor immune cells may focus more on minor antigens, potentially increasing the risk of GVHD caused by these minor differences.
• Perfect HLA Matching reduces the risk of GVHD from major HLA mismatches, but it does not eliminate the risk of GVHD

Wiskott-Aldrich Syndrome (WAS) Overview

• A rare X-linked disorder that affects males almost exclusively and is characterized by immunodeficiency, thrombocytopenia with small platelets, and eczema.

Etiology of Wiskott-Aldrich Syndrome

• Mutations in the WAS gene, located on the X chromosome, which encodes the Wiskott-Aldrich syndrome protein (WASP).
• WASP is crucial for hematopoietic cell function involved in the immune response.
• WASP plays a vital role in cellular signaling and the formation of the immunological synapse, which allows immune cells to coordinate and respond effectively to pathogens.

Epidemiology of Wiskott-Aldrich Syndrome

• Rare, with an estimated incidence of 1 in every 100,000 live births, and seen almost exclusively in males, due to its X-linked recessive inheritance pattern.
• Not limited by ethnicity or geography but is underreported due to misdiagnosis.

Pathogenesis of Wiskott-Aldrich Syndrome

• Impaired WASP protein results from mutations in the WAS gene. WASP is vital for cytoskeletal rearrangement, which is crucial for the function of T cells, B cells, and platelets.
• Cytoskeletal organization is essential for immune functions and immunological synapse formation that allows immune cells to form physical contact with their target cells.
• T cells rely on the ability to form pseudopods but have impaired ability to do so in WAS, affecting their migration, adhesion, and interaction with B cells.
• B cell homeostasis is disrupted, leading to the depletion of circulating mature B cells and a compromised humoral immune response.
• Invariant natural killer (NK) T cells are completely absent in patients with WAS, which contributes to an increased susceptibility to autoimmunity and cancer.

How iNKT Cell Dysfunction Leads to Autoimmunity in WAS

• Patients have fewer functional iNKT cells, leading to impaired regulation of autoreactive B and T cells.
• Impaired iNKT cells cannot provide adequate Treg stimulation, leading to uncontrolled immune activation and autoimmune diseases such as vasculitis, hemolytic anemia, and thrombocytopenia.
• Dysfunctional iNKT cells lead to an overactive Th1 response, promoting chronic inflammation and autoimmunity.

How iNKT Cell Dysfunction Increases Cancer Risk in WAS

• Defective iNKT cells lead to weakened anti-tumor responses, allowing malignancies like lymphoma and leukemia to develop.
• Dysfunctional iNKT cells fail to activate DCs effectively, leading to poor tumor antigen presentation and immune evasion by cancer cells.
• Chronic inflammation, due to defective immune regulation, can create an immunosuppressive tumor microenvironment, promoting cancer development.

Cytoskeletal Disruption in Platelets

• Defective WASP in megakaryocytes impairs their ability to form normal platelets, resulting in fewer and smaller platelets (microthrombocytopenia) leading to an increased risk of bleeding.

Phagocytosis and Immune Function

• Impaired phagocytic cells are impaired in their ability to move and carry out phagocytosis.

Clinical Presentation of Wiskott-Aldrich Syndrome

• Eczema caused by T-cell dysfunction, a Th2-skewed response, and a weakened skin barrier.
• Thrombocytopenia leading to easy bruising and prolonged bleeding times.
• Immunodeficiency with increased susceptibility to infections due to impaired immune cell function.

Genetics of Wiskott-Aldrich Syndrome

• Inherited in an X-linked recessive manner, with males typically affected and females usually being carriers.
• X-linked Thrombocytopenia, caused by a smaller mutation in the WAS gene, may only lead to thrombocytopenia without the full triad of symptoms seen in classic WAS.
• Wiskott-Aldrich Syndrome Type II, caused by a mutation in the WIPF1 gene, has symptoms similar to those seen in classic WAS.

Leukocyte Adhesion Deficiency (LAD) Overview

• Leukocyte Adhesion Deficiency (LAD) is an immunodeficiency disorder affecting both B and T cells.

Definition & Pathogenesis of LAD

• Defect in cellular adhesion molecules is caused by mutations in beta-2 integrins, which are essential for leukocyte movement from the bloodstream into tissues.
• Leukocytes (white blood cells), mainly neutrophils, are the cells that are most affected.
• With LAD the cells fail to exit the bloodstream and migrate to infected tissues, leading to severe immunodeficiency.

Types of Leukocyte Adhesion Deficiency

• LAD Type 1 (Most Common), caused by a mutation in the ITGB2 gene, which encodes CD18 (a subunit of β2 integrins).
• LAD Type 2, caused by a defect in fucose metabolism, preventing the synthesis of Sialyl-Lewis X (SLeX), which is a carbohydrate required for leukocyte rolling on the endothelium.
• LAD Type 3, caused by a mutation affecting beta-1, beta-2, and beta-3 integrins, leading to defective adhesion and signaling.

How the Genetic Defect in LAD Type 2 Causes Cognitive Impairment and Facial Features

• LAD Type 2 is caused by a mutation in the SLC35C1 gene, which encodes a GDP-fucose transporter.
• Defective fucosylation disrupts proper neuronal connections and leads to intellectual disability and cognitive impairment.
• Because many proteins involved in craniofacial morphogenesis rely on proper glycosylation the craniofacial development is affected leading to distinctive facial features (e.g. coarse facial features, small jaw, etc)

Mechanism of Disease

• A mutation in the beta subunit of integrins disrupts their function as adhesion molecules, leading to defective leukocyte migration.
• CD18 deficiency results in decreased expression of key integrins, such as LFA-1 and Mac-1.
• Without leukocytes being able to escape the bloodstream it leads to impaired pus formation, Abnormal inflammatory responses and Recurrent bacterial infections.

Extravasation & Its Importance

• Leukocyte migration (extravasation) is essential for immune function and follows four major steps: rolling, adhesion, transmigration, and migration to infection site.
• The endothelium expressing selectins on leukocytes.
• Defective rolling occurs in LAD Type 2, where leukocytes lack Sialyl-Lewis X and cannot interact with selectins.
• Defective adhesion occurs in LAD Type 1, where leukocytes cannot adhere to the vessel wall, integrins do not bind and there is a prevention of firm adhesion of leukocytes to endothelial cells.

How LAD Disrupts Extravasation

• LAD Type 1: Mutation in CD18 prevents firm adhesion, so phagocytes cannot stop rolling and migrate into tissues.
• LAD Type 2: Loss of Sialyl-Lewis X prevents rolling, so leukocytes never slow down enough to adhere.
• This leads to uncontrolled bacterial and fungal infections and delayed umbilical cord separation.

Genetics of LAD

• Both LAD Type 1 and Type 2 are inherited in an autosomal recessive pattern. An affected individual must inherit two copies of the mutated gene (one from each parent).

Delayed Umbilical Cord Separation

• Delayed umbilical cord separation is a classic finding.
• LAD II Doesn’t commonly cause delayed umbilical cord separation but presents with other features like intellectual disability and growth retardation.

Mechanisms of Disease: Myasthenia Gravis Overview

• Autoimmune disease that is caused by autoreactive antibodies that alter acetylcholine receptors (AChRs) at the neuromuscular junction.
• Causes muscle weakness that worsens with activity and improves with rest.

Symptoms of Myasthenia Gravis

• Diplopia and ptosis
• Altered facial expression (difficulty smiling or frowning).
• Difficulty swallowing (dysphagia), impaired speech (dysarthria).
• Generalized weakness, difficulty with tasks like lifting or walking.
• Shortness of breath (dyspnea).

Primary symptom of Myasthenia Gravis

• Muscle weakness that worsens with activity and improves with rest and Fatigued muscles due to tasks such as walking, talking, or lifting objects.

Pathophysiology of Myasthenia Gravis

• Is a Type II hypersensitivity reaction, meaning that the immune system directly targets and damages the body’s own tissues where.
• Autoantibodies block or alter the function of ACh receptors, preventing acetylcholine from binding and initiating muscle contraction.
• Resulting in: Complement Activation, Alternative Autoantibodies and Paraneoplastic Syndrome.

Myasthenic Crisis

• A life-threatening complication in which the muscles that control breathing become severely affected resulting in:
• Respiratory failure
• Requires immediate medical intervention, such as ventilator support is needed.

Etiology and Pathogenesis of Myasthenia Gravis

• Autoimmune that is caused by autoreactive antibodies (produced) that alter acetylcholine receptors (AChRs) at the neuromuscular junction.
• Autoantibodies, either block the receptor, alter its structure, or destroy the receptor entirely on receptors.
• The progressive muscle contraction becomes impaired because acetylcholine cannot effectively activate the muscle.
• These antibodies may also activate the complement system, which is a part of the immune system that causes inflammation and damage to the muscle cells, further reducing the number of functional acetylcholine receptors.

Epidemiology of Myasthenia Gravis

• Young women under the age of 40 are most commonly affected.
• Older men in their 60s and 70s are also frequently affected.
• Myasthenia gravis is not inherited nor is it communicable and the condition effects people of all ethnic backgrounds.
• Neonatal myasthenia gravis can occur if a fetus acquires anti-AChR antibodies from the mother.

Overview of Rheumatoid Arthritis (RA)

• Chronic inflammatory disorder primarily affecting the joints but can also impact other organ systems such as the skin and lungs
• Comes from rheumatism, which broadly refers to musculoskeletal disorders.
• The term "rheumatoid" comes from rheumatism, which broadly refers to musculoskeletal disorders.

Etiology and Epidemiology of Rheumatoid Arthritis

• Unknown Origin: immune system abnormalities play a significant role in its development in combination with genetic predisposition
• The primary genetic risk factors for RA are the HLA-DRB1 and HLA-DR4 alleles, which are immune system-related genes.
• RA is more common in women than in men, typically starting between the ages of 30 and 50

Pathogenesis of Rheumatoid Arthritis

• Autoimmune disease: The body mistakenly attacks its own tissues, particularly the synovial membrane (lining of joints) with activation of many immune cells
• Macrophages and fibroblasts ,Cytokines ( such as TNF-alpha, IL-6, and IL-1.) become activated and contribute to the destruction of cartilage and bone.
• Synovial hyperplasia (overgrowth of the synovial membrane) is a hallmark that Contributes to the formation of a pannus: an invasive tissue made of inflammatory cells, fibroblasts, and myofibroblasts.

Primary Role of the Pannus in RA

• The pannus secretes:Proteases and other inflammatory mediators, Degrades cartilage and contributes to bone erosion, leading to joint damage

Mechanisms of Joint Damage in RA

• Binding of antibodies (like Rheumatoid factor (RF), ACPA ) and their targets leads to the formation of immune complexes, which accumulate in the synovial fluid and activate the complement system, further promoting inflammation.
• TNF-alpha, IL-1, and IL-6 are major inflammatory cytokines that: Promote the proliferation of synovial cells and immune cells, Trigger the breakdown of cartilage and bone matrix, Cause angiogenesis to support ongoing inflammation

Clinical Manifestations of RA

• Typically affects multiple joints, often in a symmetrical pattern, Joint swelling, pain, redness, and warmth occur during flares.
• Over time, joint damage can result in deformities such as: Ulnar deviation of fingers, Buttonhole deformity and Swan-neck deformity. A synovial cyst can form behind the knee

Extra-Articular Manifestations of RA

• Fever, fatigue, weight loss, muscle weakness are results of Non-specific inflammation in a Systemic Symptoms
• Rheumatoid Nodules develop over pressure points
• Vasculitis contributes to atherosclerosis, heart attack, and stroke and a Interstitial lung disease affect lung involvement.
• Anemia of chronic disease is common
• The liver produces hepcidin, which lowers iron levels in the bloodstream

Hashimoto's Thyroiditis: Mechanisms of Disease

• Is autoimmune disorder that can cause hypothyroidism although may initially cause hyperthyroidism
• More common in women, especially between the ages of 30 and 50
• The condition also tends to occur more frequently in patients with other autoimmune disorders

Symptoms of Hashimoto’s Disease

• Occurs in progressive stage where there becomes to be a lack of thyroid hormones.
• Fatigue, Weight gain, Intolerance to Cold, Joint and muscle pain, Thinning hair and Irregular periods.

Pathogenesis (Disease Progression)

• Autoimmune where Immune system attacks follicular cells which trigger immune systems and create genetic component.
• T helper cells stimulate the B cells in the lymph node to start proliferating and differentiate into plasma cells, which produce specific auto antibodies against these auto antigens. In Hashimoto thyroiditis, these plasma cells and helper cells enter the circulation and reach the thyroid gland and begin to block functions.