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Immunology

Immunoproliferative Diseases

Let’s shift our focus from an immune system that is over-reacting (hypersensitivity) or misguided (autoimmunity) to one where the immune cells themselves become the enemy. This is the realm of immunoproliferative diseases, which are essentially cancers of the immune system

At the heart of this topic is a group of disorders called monoclonal gammopathies. To grasp this, we first need to appreciate that a normal immune response is polyclonal. When you get a flu shot, thousands of different B-cell clones are activated, each producing its own unique antibody against different parts of the virus. On a lab test, this healthy response appears as a broad, diverse smear of different gamma globulins

A monoclonal gammopathy is the polar opposite. It’s what happens when a single B-cell or plasma cell clone goes rogue, ignores all growth signals, and begins to divide uncontrollably. This malignant clone becomes a massive, unregulated factory that floods the body with one single, identical, and functionally useless type of immunoglobulin. In the lab, we call this abnormal antibody the M-protein or paraprotein. Our primary job as Medical Laboratory Scientists is to detect, identify, and quantify this M-protein, which serves as the tumor marker for these diseases

Key Players: Myeloma vs. Waldenström’s

While there are several types of monoclonal gammopathies, two stand out as the classic examples you must know. They are defined by which cell has become cancerous and, most importantly, which type of M-protein it produces

Plasma Cell Myeloma (Multiple Myeloma): The Bone Invader

This is the most common and aggressive of the malignant monoclonal gammopathies

  • The Malignant Cell: A terminally differentiated plasma cell that proliferates in the bone marrow
  • The M-Protein: Most commonly IgG, followed by IgA. An IgM myeloma is extremely rare
  • The Core Problem: The cancerous plasma cells cause disease by:
    1. Invading the Bone Marrow They “crowd out” normal blood cell production, leading to anemia and susceptibility to infection
    2. Destroying Bone They secrete factors that cause “punched-out” lytic lesions in the bones, leading to fractures and a dangerous release of calcium into the blood (hypercalcemia)
    3. Damaging the Kidneys The overproduced monoclonal light chains (called Bence Jones proteins) are toxic to the kidneys and are a major cause of renal failure

Waldenström Macroglobulinemia: The Blood Thickener

This is a rarer, more slow-growing disorder that is considered a type of lymphoma

  • The Malignant Cell: A lymphoplasmacytic cell, which is an intermediate cell between a mature B-cell and a plasma cell
  • The M-Protein: The defining feature is that the M-protein is always IgM. The “M” stands for “Macro,” a huge pentameric molecule
  • The Core Problem: The main issue in Waldenström’s is not bone destruction, but hyperviscosity syndrome. The massive amount of large IgM protein literally makes the blood thick and syrupy. This “sludging” of the blood impairs circulation, leading to blurry vision, headaches, and bleeding

Lab’s Role: Hunting for the M-Protein

The diagnosis of these diseases is impossible without the clinical lab. We use a two-step process to find and identify the M-protein

  1. Screening with Serum Protein Electrophoresis (SPEP) This is the first-line test. We separate the patient’s serum proteins by charge. A normal result shows a broad, smear-like curve in the gamma region, representing the polyclonal antibodies. In a monoclonal gammopathy, we see a tall, sharp, narrow spike in this region. This M-spike is the visual evidence of the monoclonal protein flooding the patient’s system

  2. Identification with Immunofixation Electrophoresis (IFE) The SPEP shows us that a spike is there, but IFE tells us what it is. This test uses specific antisera to identify the exact heavy chain (G, A, or M) and light chain (kappa or lambda) of the M-protein. An IgG kappa M-protein points to myeloma, while an IgM kappa M-protein is diagnostic for Waldenström’s

A Crucial Note: MGUS

It’s vital to know that not every M-spike means cancer. Monoclonal Gammopathy of Undetermined Significance (MGUS) is a common, pre-malignant condition where a small M-protein is found, but the patient has none of the symptoms of myeloma or Waldenström’s. These patients are not treated but are monitored closely, as a small percentage will eventually progress to a malignant disease