Graft Versus Host Disease (GVHD)

Graft Versus Host Disease (GVHD)

• Graft versus host disease (GVHD) happens when immune cells from a transplant (graft) see the recipient's (host) body as foreign and attack it
• GVHD requires immunologically competent cells to be transplanted into an immunodeficient recipient
• GVHD can occur after bone marrow transplants, lymphoid-rich solid organ transplants (e.g., liver), and unirradiated blood transfusions

Epidemiology of GVHD

• Acute GVHD occurs in up to 50% of stem cell transplant recipients from HLA-matched siblings
• GVHD complications lead to death in over 10% of stem cell transplant patients
• GVHD risk is higher in unmatched donors, even though HLA matching is essential

Organs Affected by GVHD

• The skin, GI tract, and liver are commonly involved in GVHD, with occurrence rates of 70-74%, 44%, and variable percentages, respectively
• The most common skin symptom is an itchy or painful maculopapular rash, usually on the palms, soles, and nape of the neck
• GI symptoms include diarrhea, nausea, and vomiting
• Liver involvement results in elevated bilirubin and alkaline phosphatase

Pathogenesis of GVHD

• Donor T cells recognize recipient cells as foreign and attack epithelial cells in the skin, liver, and gut
• Immune cells distinguish self from non-self using major histocompatibility complex (MHC) proteins, also called human leukocyte antigens (HLA)
• MHC Class I is on all nucleated cells, and MHC Class II is on antigen-presenting cells
• Minor histocompatibility antigens can cause an immune response even in HLA-identical individuals

Key Elements for GVHD to occur

• The graft must contain immune cells, as in hematopoietic stem cell transplants (from bone marrow, peripheral blood, or umbilical cord blood)
• The host's immune system must be suppressed
• The host is immunologically different from the donor, meaning the grafted immune cells recognize the recipient’s HLA antigens as foreign

GVHD Mechanism

• Host dendritic cells present antigens to donor helper T cells in lymph nodes
• Donor helper T cells recognize the antigens as foreign and activate
• Activated TH1 cells release cytokines (Interleukin-2 (IL-2) and Interferon-gamma (IFN-γ)) enhancing antigen presentation and macrophage activation and promoting inflammation/tissue destruction
• Cytotoxic T cells recognize host antigens and release perforin and granzymes triggering apoptosis

Wiskott-Aldrich Syndrome

• Wiskott-Aldrich Syndrome (WAS) is a rare X-linked disorder with immunodeficiency, thrombocytopenia, and eczema
• WAS is caused by mutations in the WAS gene that is involved in cellular signaling and immunological synapse formation
• The incidence of WAS is about 1 in 100,000 live births, mainly affecting males

Pathogenesis of WAS

• Mutations in the WAS gene result in an abnormal WASP protein, impairing cytoskeleton formation
• This causes insufficient interaction between T cells and other cells
• T cells have impaired migration, adhesion, and interaction with B cells due to the mutation
• B cell homeostasis disrupted leading to depletion of circulating mature B cells

iNKT Cells and WAS

• Invariant natural killer T cells are absent in WAS patients, increasing risk for autoimmunity and cancer
• iNKT cell dysfunction disrupts immune tolerance leading to autoimmunity and weakens tumor surveillance resulting in increased cancer risk
• Reduced iNKT cells lead to impaired regulation of autoreactive B and T cells and produce less regulatory cytokines

Role of iNKT Cells in Autoimmunity

• iNKT cells enhance Treg function, suppressing self-reactive immune responses
• Impaired iNKT cells fail to provide adequate Treg stimulation leading to uncontrolled immune activation
• Dysfunctional iNKT cells lead to an overactive Th1 response, promoting chronic inflammation and autoimmunity

Role of iNKT Cells in Cancer

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

Cytoskeletal Disruption in Platelets with WAS

• Due to defective WASP platelets are fewer and smaller (Microthrombocytopenia), thus leading to bleeding risk

Clinical Presentation of WAS

• Patients with WAS typically present with Eczema
• This happens dues to dysfunction (T-cell, B-cell, etc) leads to chronic skin inflammation, itching, and increased susceptibility to skin infections
• Thrombocytopenia: Low platelet count, so in result easy bruising, prolonged bleeding
• Immunodeficiency because of impaired T cells and B cells cause increased susceptibility to infections

Genetics of WAS

• WAS is inherited in an X-linked recessive manner, mainly affecting males
• X-linked Thrombocytopenia is like WAS but a milder form due to a smaller mutation in the WAS gene
• Wiskott-Aldrich Syndrome Type II is caused by a mutation in the WIPF1 gene and has similar symptoms

Leukocyte Adhesion Deficiency (LAD)

• Leukocyte Adhesion Deficiency (LAD) is an immunodeficiency disorder that affects leukocytes
• LAD is caused by a defect in cellular adhesion molecules due to a mutations in beta-2 integrins, because of the disrupted WBCs can't exit the blood to fight off infections,

Types of LAD

• LAD Type 1 is due to a CD18 mutation, the key is leukocytes cannot adhere to endothelial surfaces
• LAD Type 2: Is due to an absence of Sialyl-Lewis X, the key is that patients exhibit a absence of E selectin
• LAD Type 3: Defect in beta integrands - 1,2,3. The key is the platelets as well as WBCs are both affected

Epidemiology of LAD

• LAD Type 1 affects 1 in 1 million people annually
• LAD one reveals recurrent infections in 93% and poor wound healing in 86%

Pathogenesis LAD

• Defect affects protein functions as adhesion molecules, reducing expression of LFA, one, Mac, one, polypeptides
• NK cells are not affected
• Patients exhibit inability to form pus and has abnormal inflammatory responses with recurrent bacterial infections
• Late separation of umbilical cord (more than 30 days) + reoccurring infections of skin and mucosa are signs to consider for LAD
• Impaired wound healing and poorly formed, thin, bluish scars

Extravasation & LAD

• Leukocyte migration (extravasation) is essential for immune function
  • Rolling - the initial step; defective in LAD Type 2
  • Adhesion - Defective in LAD Type 1
  • Transmigration (Diapedesis)
  • Migration to Infection Site
• LAD Type 1 is a Mutation in CD18, this prevents firm adhesion
• LAD Type 2 loss of Sialyl-Lewis X prevents rolling

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. It is a GDP-fucose transporter
• Fucosylation plays essential role in neuronal signaling, memory, and cognitive function as well as normal facial features.
• Defective fucosylation disrupts proper neuronal connections, and normal facial feature, leading to intellectual disability and cognitive impairment.

Myasthenia Gravis Overview

• Myasthenia gravis is an autoimmune disorder that attacks neuromuscular junctions
• AchR Autoantibodies cause it and prevent Muscle Contraction from the nerves because of blocked or altered receptors at the neuromuscular junction
• Effects are seen mostly in young women under 40 and Myasthenia gravis not inherited

Symptoms of Myasthenia Gravis

• Muscle weakness is common
• Weakness of the eye muscles
• Blurred vision
• Difficulty swallowing
• Impaired speech also seen

Autoimmune nature of MG

• MG is a Type II hypersensitivity reaction The immune system directly targets and damages to receptors.
• Autoantibodies made and used to impair muscle control
• Can also activate complement system, which in turn leads to Inflammation
• Thymomas may induce autoantibodies that can trigger MG

Myasthenic Crisis

• Myasthenic crisis is life-threatening when Muscular control over breathing is lost requiring ventilator support

Rheumatoid Arthritis Overview

• Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects the joints and other organ systems
• RA Etiology is unknown but genetic and also environmental factors can increase chances
• Genetics: HLA DRB one & Tumor necrosis factor increase risk

Pathogenesis of RA

• Cellular & Humoral Immune Responses causes it leads to autoantibodies (Rheumatoid factors)
• Synovial hyperplasia is a hallmark sign with intense activation in joint tissues
• Ra causes Inflammation: which leads to joint pain, swelling, plus destruction of joints
• Cytokines deregulate the balance of cartilage formation/degradation

Role of the Pannus RA:

• Pannus is an abnormal growth tissue
• Pannus invades surrounding tissues and contributes to joint destruction.
• Pannus releases proteases (enzymes that break down proteins) and other inflammatory mediators that degrade cartilage and bone in the affected joint. This leads to progressive damage in the joint, causing pain, deformities, and loss of function.
• Synovial cells secrete proteases that break down Articular cartilage

immune complex formation

• Rheumatoid factor (RF) that are IgG which target altered IgG forms immune complexes that accumulate in synovial fluid
• ANti-cyclic citrullinated Peptide antibody happens with modified proteins and also accumulate
• Ultimately Chronic leads to inflammation which causes angiogenesis and increases joint destruction
• Angiogenesis- Allows more inflammatory cells can arrive