by Gary E. Myerson, M.D., F.A.C.R.
From ATLANTA Medicine, 2012, Rheumatology, Vol. 83, No. 3
Centuries ago, geography itself served as the primary barrier to disease exposure. But man’s exploration of the planet, enhanced by progressive technological expertise, has permitted both exposure to and expansion of diseases worldwide. However, our increasing knowledge of science overall and the specific components of the immune response has led to numerous diseases either being reduced or eliminated.
The immune response is an ancient system. Certain components, however, have not significantly changed in the millions of years of existence of species with vertebrae. The homo-sapiens and homo-erectus, nearly 250,000 years ago, possessed an immune system similar to ours. Innate immune response has been present throughout this entire period. It has been our “equalizer” in dealing with the microscopic environment that envelops us. We have made” friends” with many microbes, resulting in relationships that are symbiotic, while others are indeed antagonistic or parasitic. It is this inherent, genetically provided, innate response that is our defense against invaders both physically and chemically. The Adaptive or acquired immune response, our body’s ability to develop antibodies, has allowed us to improve or enhance our own innate immune response. Biologic therapy with monoclonal antibodies now allows us to manipulate specific proteins important in the immune response.
Our first line of defense includes the skin and lining surfaces of the internal body organs. There are enzymes in body secretions including lysozymes, phospholipases and defensins, which disrupt cell membranes promoting cell death. Periodically, the anatomical barriers are penetrated and an “acute inflammatory reaction” follows. The release of acute phase reactants: transferrin, CRP, interferon and interleukins, results in the cardinal signs of inflammation: calor/hot, rubor/red, dolor/painful and tumor/swelling. The phagocytic cells including the neutrophils, macrophages, dendritic cells, natural killer or NK cells and eosinophils are the major players in identifying and responding to microscopic invaders. The phagocytic cells are directed to specific locations via cytokines, protein communicators of inflammation that identify, engulf and destroy pathogens.
These cells are primary players of the innate immune response – the oldest form of the host defense system. The innate immune response is triggered when microbes
(bacteria, virus and fungi) are detected. On or attached to the cell membranes of pathogens are commonly shared patterns (PAMPS). These include lipopolysaccharides(LPS), lipoteichoic acid, flagellin, RNA of viruses, amongst others. These molecules are recognized by receptors on the phagocytic cells called pattern recognition receptors (PRR).
One large group of the PRRs is a specific subgroup entitled Toll-like receptors (TLR). These highly specific receptors, numbered 1 through 13, identify and bind PAMPS, resulting in cytokine production triggering inflammation.
The complement cascade is also a major component of the innate immune response. The Complement system serves as an identifier and clearing house of pathogens by promoting vascular permeability, recruitment of phagocytic cells and ultimately the opsonization of bacteria and immune complexes. Opsonization refers to the coating and subsequent marking of bacteria for future destruction.
A large component of opsonization occurs in the spleen, which is why splenectomized patients particularly need vaccinations. Complement CH50 is a measure of total complement activity. Individuals with active autoimmune disease may have low levels of C3 and C4 due to overactivity of the complement cascade. This results in immune complex formation and the consumption of complement.
When the inflammation resolves, complement levels return to the normal range. Therefore, low levels of CH50 and C3 and C4 reflect active autoimmune disease, but higher levels do not.
Innate immune response is a non-antigen specific, immediate reaction. It does not produce immunological memory. For long-term protection, there is our adaptive or acquired immune response. Immunological memory is accomplished by the development of antibodies as our ready reserve defense force. Subsequent encounters with the same organism result in an enhanced response. There is a period of approximately 10-14 days for antigen-specific antibodies to be developed.
All cells of the immune system have their origin in the bone marrow. The myeloid series primarily produces the cells of the innate immune system including the neutrophils, monocytes and dendritic cells. While the lymphoid series(lymphocytes) produces cells for the acquired or adaptive immune response, the T cells undergo differentiation into their distinct types under the influence of the thymus gland. B cells become mature in the lymph nodes and the spleen.
There is a tremendous amount of interaction between both systems, utilizing the myeloid series innate immune system for stimulation and activation of the acquired immune response. T-cells are involved in the cell-mediated immune response. They have no cytotoxic activity and do not kill infected cells or clear pathogens directly. Instead, they control the immune response by directing other cells to perform these tasks.
The cytokines the T-cells produce are the “protein communicators of inflammation.” Three important cytokines include TNF alpha and interleukins IL-1 and IL-6. These have been identified as primary players in autoimmune diseases including rheumatoid arthritis, psoriasis and psoriatic arthritis, Ankylosing spondylitis and inflammatory bowel disease(specifically Crohn’s disease) as well as Uveitis and Sarcoidosis.The T-cell begins as a “naïve” cell, which requires antigen presentation in order for it to become activated. These antigen-presenting cells (APC) include the macrophage, dendritic cell and the B cell. The APC presents the antigen to the naive T-cell via its major histocompatibility complex (MHC) T-cell receptor (TCR). Depending on the APC cell type and the predominance of surrounding cytokines, T-cells differentiate in one of four directions:
1. TH 1 cells. APCs include the macrophages and dendritic cells. IL 12 and interferon (INF) gamma are the cytokines that drive differentiation. This type of T-cell usually develops from exposure to intracellular bacteria, fungus or viruses.
2. TH 17 cells. Neutrophils; IL 23, IL-1, IL-6. Usually from exposure of extracellular bacteria and fungi.
3. TH 2 cells. Eosinophils and basophils. IL-4. Usually from exposure to parasites.
4. T reg (regulatory) cells. Response to self-antigens. IL-10 and TGF beta. Down regulates autoimmune response. There is however cross stimulation and inhibition
depending on which interleukin predominates. For instance, IL6 inhibits TGF beta, therefore driving TH 17 production and reducing T reg production, Alternatively, IL-4 while driving TH2 production inhibits TH 17 production.
Cell membranes of T-cells have cluster differentiation (CD) glycoproteins CD4 and CD8. Cells with the CD4 glycoprotein are referred to as helper cells, and those with
CD8 glycoprotein are referred to as cytotoxic T-cells. CD4 helper cells assist in the maturation of B cells into plasma cells and memory B cells. They also assist in the activation of cytotoxic T-cells and macrophages. Cytotoxic CD8 cells destroy viral-infected and tumor cells and also play a role in transplant rejection.
The humoral immune response is directed by B lymphocytes (B cells) differentiating into plasma cells which produce antibodies. The B cell develops through several stages. A B cell begins as a progenitor cell, then progresses to a pro-B cell and finally a pre-B cell. At this point, it leaves the bone marrow to mature in the lymph nodes and spleen where it becomes exposed to the pathogenic environment. As it matures, it develops three surface receptors – Blys, TACI and the B-cell receptor (BCR). When these receptors are bound, the cell matures and continues to exist. Failure to bind these receptors results in apoptosis or programmed cell death. This has become a recent important discovery since Benlysta, a new drug for the treatment of lupus, works by inhibiting Blys, the cell surface receptor.
These immunoglobulins are a hallmark of our defense system. We’re aware that deficiencies in any one of them or their subtypes results in the development of recurrent infections. Specific types of intravenous and subcutaneous gammaglobulin are available for those deficiency states. Memory B cells are formed from activated B cells that are specific to the antigen encountered during the primary immune response. These cells are capable of living “a long time” and can respond quickly following a second exposure to the same antigen.
B-1 cells and B-2 cells, B-1 cells express high levels of IgM greater than IgG and
are polyspecific – meaning that they have the ability to produce low-level response to many antigens.
Unlike the T cell, the B cell does not need the antigen presented to it. It recognizes the antigen in the blood or lymphatic system and engulfs it. It can then act as an antigen-presenting cell itself by displaying its antigen bound to its unique MHC on the cell surface allowing a T-cell to bind to it. Through a co-stimulatory mechanism necessitating a second binding site to be activated, cytokines can then be released. The cytokines released by that T-cell further propagate the B cell into its mature state, producing plasma cells and more immunoglobulin. Antibodies bind to their specific antigens forming immune-complexes. These complexes are then “cleaved” by the complement system and eliminated through the reticuloendothelial system.
Autoimmune diseases result from aberrant antibody production. These autoantibodies are actually produced on a regular basis by all individuals. Fortunately, more than 90 percent of them undergo spontaneous apoptosis and never progress. Anti-B cell medications predominantly work by interfering with the B cell during its maturation. Examples of these medications are being utilized in both oncology and rheumatology.
A baby’s immune defenses are passively transferred from the mother at birth. The baby’s own immune defenses take approximately three months to begin to function.
