11.4 Immune System Disorders

Immune System Disorders

The immune system, our body's defense mechanism, can sometimes malfunction, leading to various disorders. These include immunodeficiencies, autoimmune diseases, and allergies. Each affects the body differently, from weakening our defenses to attacking our own tissues.

Understanding these disorders is crucial for grasping how the lymphatic and immune systems work together. Whether it's the overreaction in allergies or the self-attack in autoimmune diseases, these conditions highlight the delicate balance our immune system must maintain for optimal health.

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Categorization and Immunodeficiencies

Immune system disorders fall into three broad categories: immunodeficiencies, autoimmune diseases, and hypersensitivity reactions (allergies). Each represents a different type of immune malfunction.

Immunodeficiencies are conditions where the immune system is compromised or weakened, leaving the body more susceptible to infections. They come in two forms:

• Primary immunodeficiencies are inherited disorders caused by genetic mutations that affect the development or function of immune cells. These are present from birth, even if symptoms don't appear right away.
  • Severe combined immunodeficiency (SCID) affects both B and T lymphocytes, leaving individuals with virtually no adaptive immune defense. Without treatment (typically a bone marrow transplant), even minor infections can be fatal.
  • X-linked agammaglobulinemia (XLA) results from a failure of B cells to mature, meaning the body produces little to no antibodies. It's X-linked, so it predominantly affects males.
• Secondary (acquired) immunodeficiencies develop later in life due to external factors that suppress immune function.
  • Causes include malnutrition, immunosuppressive medications (like chemotherapy drugs), and infections. HIV/AIDS is the most well-known example: HIV specifically targets and destroys $CD4^+$ T helper cells, progressively crippling the adaptive immune response.

Autoimmune Diseases

Autoimmune diseases occur when the immune system mistakenly attacks the body's own tissues. The core problem is a failure of self-tolerance, the mechanism that normally prevents immune cells from reacting to self-antigens. When this breaks down, the body produces autoantibodies or activates T cells against its own cells, causing chronic inflammation and tissue damage.

Common autoimmune diseases include:

• Rheumatoid arthritis (RA) targets the synovial membranes of joints
• Systemic lupus erythematosus (SLE) can affect multiple organ systems
• Multiple sclerosis (MS) attacks the myelin sheath around neurons in the CNS
• Type 1 diabetes destroys insulin-producing beta cells in the pancreas
• Hashimoto's thyroiditis targets the thyroid gland, leading to hypothyroidism

These diseases vary widely in which tissues they attack, but they all share that same underlying problem: the immune system can no longer tell "self" from "non-self."

Allergic Reactions

Causes and Mechanisms

Allergic reactions are type I hypersensitivity responses where the immune system overreacts to normally harmless substances called allergens. Common allergens include pollen, dust mites, animal dander, and certain foods (peanuts, shellfish).

The allergic response unfolds in two phases:

1. Sensitization (first exposure): The immune system encounters the allergen for the first time and mistakenly identifies it as a threat. B cells produce IgE antibodies specific to that allergen. These IgE antibodies bind to the surface of mast cells (in tissues) and basophils (in blood), essentially "arming" them. No symptoms occur during this phase.

2. Re-exposure (subsequent encounters): When the same allergen enters the body again, it cross-links the IgE antibodies already sitting on mast cells and basophils. This triggers degranulation, the rapid release of histamine and other inflammatory mediators. These chemicals cause the familiar allergy symptoms: vasodilation, increased mucus production, smooth muscle contraction, and increased vascular permeability.

Symptoms and Anaphylaxis

Symptoms of allergic reactions range from mild to severe:

• Mild to moderate: itching, redness, swelling, hives, runny nose, watery eyes, sneezing, coughing
• Severe: difficulty breathing, wheezing, significant swelling

Anaphylaxis is the most dangerous allergic reaction. It's a systemic response where massive histamine release causes:

• Widespread vasodilation, leading to a sharp drop in blood pressure (anaphylactic shock)
• Severe bronchospasm and throat swelling, restricting the airway
• Rapid onset, often within minutes of exposure

Anaphylaxis requires immediate injection of epinephrine (adrenaline), which counteracts these effects by constricting blood vessels, relaxing airway smooth muscle, and increasing heart rate. This is why individuals with known severe allergies carry EpiPens.

Autoimmune Disorders in Detail

Rheumatoid Arthritis (RA)

Rheumatoid arthritis is an autoimmune disorder that primarily targets the synovial membrane lining the joints. The immune system attacks this membrane, causing chronic inflammation that leads to pain, stiffness, swelling, and progressive joint destruction. Unlike osteoarthritis (which is wear-and-tear), RA is driven by immune activity and typically affects joints symmetrically (both hands, both knees).

Treatment involves a layered approach:

• NSAIDs (nonsteroidal anti-inflammatory drugs) reduce pain and inflammation
• DMARDs (disease-modifying antirheumatic drugs) like methotrexate slow disease progression by broadly suppressing immune activity
• Biological agents such as TNF inhibitors target specific inflammatory molecules rather than suppressing the whole immune system
• Physical and occupational therapy help maintain joint function and manage daily activities

Systemic Lupus Erythematosus (SLE or Lupus)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can affect virtually any organ system, including the skin, joints, kidneys, blood cells, brain, heart, and lungs. This makes it one of the most unpredictable autoimmune diseases.

The hallmark of lupus is the production of autoantibodies (particularly anti-nuclear antibodies, or ANAs) that form immune complexes. These complexes circulate in the blood and deposit in tissues throughout the body, triggering inflammation and damage wherever they settle. This is why lupus can affect so many different organs.

Treatment depends on severity and which organs are involved:

• Mild cases may be managed with NSAIDs and antimalarial drugs (hydroxychloroquine)
• More severe cases require corticosteroids, immunosuppressants (cyclophosphamide), or targeted biological therapies (belimumab)
• Regular monitoring is essential because lupus flares unpredictably, and organ damage (especially kidney involvement, called lupus nephritis) can accumulate over time

Immune System in Transplantation and Cancer

Transplant Rejection

Transplant rejection occurs when the recipient's immune system recognizes the transplanted organ as foreign and mounts an immune response against it. The key players in this recognition are MHC molecules (major histocompatibility complex), also called HLAs (human leukocyte antigens) in humans. These are the surface proteins that T cells use to distinguish self from non-self. The greater the mismatch in HLAs between donor and recipient, the higher the risk of rejection.

There are three types of transplant rejection, classified by timing:

• Hyperacute rejection occurs within minutes to hours. Pre-existing antibodies in the recipient immediately attack the donor tissue. This is rare today because of pre-transplant crossmatching.
• Acute rejection develops within days to weeks. The recipient's T cells recognize foreign HLAs on the donor organ and mount a cell-mediated immune response.
• Chronic rejection occurs months to years after transplantation. A slow, ongoing immune response gradually damages the transplanted organ, often through fibrosis of blood vessels.

To prevent rejection, patients take immunosuppressive drugs for the life of the transplant. These include calcineurin inhibitors (cyclosporine, tacrolimus), antimetabolites (mycophenolate mofetil), and corticosteroids. The trade-off is that suppressing the immune system also increases vulnerability to infections and certain cancers.

Cancer Immunology and Immunotherapy

The immune system has a complicated relationship with cancer. On one hand, it performs immunosurveillance, constantly scanning for and eliminating abnormal cells before they can form tumors. On the other hand, cancer cells that survive this screening have often evolved ways to evade or suppress immune detection, a process called immunoediting.

Cancer cells evade the immune system through several strategies, including downregulating MHC expression (so T cells can't recognize them) and expressing checkpoint molecules like PD-L1 that essentially tell T cells to stand down.

Cancer immunotherapy works by removing these brakes or boosting the immune system's ability to fight tumors:

• Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1/PD-L1) block the "off switches" that cancer cells exploit, allowing T cells to attack the tumor
• Adoptive cell therapy (CAR T-cell therapy) involves engineering a patient's own T cells to recognize specific tumor antigens, then infusing them back into the patient
• Cancer vaccines stimulate the immune system to target tumor-specific antigens

The success of immunotherapy depends on several factors: how immunogenic the tumor is (how many recognizable antigens it displays), whether tumor-infiltrating lymphocytes are already present, and how strongly the tumor microenvironment suppresses immune activity. Not all cancers respond equally to these therapies, which is why immunotherapy works dramatically well for some patients but not others.