Immunology
LYMPHOID STRUCTURES
Anatomy of the Immune System
Primary lymphoid organs are organs that function as “housing” for immature progenitor cells to generate, mature, and educate new lymphocytes in an antigen-independent manner. The main examples of these organs include the Bone marrow for B cells and the Thymus for T cells.
Bone marrow is a critical primary lymphoid organ. It consists of two primary types: red marrow and yellow marrow. Red marrow is the bone marrow parenchyma and contains the hematopoietic stem cells, which function in the formation of all blood cell lines, including B and T cells. Yellow marrow is the bone marrow stroma (supportive tissue) and contains mostly fat.
The thymus is the other primary lymphoid organ. Its embryologic origin is the epithelium of the third branchial pouch. Structurally, it is an encapsulated, bilobed organ situated in the anterior mediastinum. During early childhood, the thymus is large and is easily seen on a chest radiograph. However, as the individual ages, there is a natural regression and atrophy of the thymic tissue, and it becomes “invisible” on a chest film. The main physiologic immune function of the thymus is to act as the T cell classroom for differentiation and maturation, which occur as cells go from the outer cortex to the inner medulla of the thymus.
Cortex: High cellular density with packed immature T cells awaiting positive (functional) selection. Positive selection ensures that the T cells will have the bare minimum functionality of binding the cell surface proteins major histocompatibility complex class I (MHC I) or II. Of note, most immature T cells that undergo this process never make it past this step and subsequently undergo apoptosis. It is of critical importance that these thymocytes are able to bind MHC. When mature, they will bind MHC I if they differentiate into CD8 + T cells and MHC II if they differentiate into CD4 + T cells.
Corticomedullary junction: In this region, T cells undergo negative selection. Negative selection destroys cells that see the body's own normal antigens as foreign invaders. Negative selection is highly important in preventing autoimmune disease by destroying T cells that could potentially start an attack on the body's own cells. A T cell that has made it through positive selection is presented with self-antigen. If the specificity of binding is too strong, an apoptotic signal will be given to that particular T cell. Of note, some autoreactive T cells are able to make it through the negative selection phase, but are eliminated by peripheral mechanisms (e.g., anergy, regulatory T cells). However, if peripheral mechanisms also fail, then this sets the stage for potential predisposition to autoimmunity.
Medulla: Pale, low cellular density with mature T cells having already gone through positive and negative selection. This area also contains Hassall corpuscles, which are remnants of apoptosed T cells seen on histology.
Secondary lymphoid organs are sites where lymphocytes undergo differentiation (increased specificity) and clonal expansion (increased number) in an antigen-dependent fashion (meaning differentiation and expansion occurs when an invader is thought to be present). Examples of secondary lymphoid organs include lymph nodes, spleen, tonsils, adenoids, and mucosa-associated lymphoid tissue (MALT).
Lymph nodes (Fig. 6-1) are encapsulated and trabeculated secondary lymphoid organs with many afferent vessels and single/few efferents (“many ways in and only one way out!”). The specific functions are determined by anatomic position within the node (cortex, medulla, and paracortex areas).
Figure 6-1 A, Lymph node illustration, showing the outer portion (cortex) with follicles containing B cells, the paracortex where B and T cells enter from the blood, and the innermost portion (medulla). B, Histologic staining of a lymph node showing primary lymphoid follicles, paracortex, and germinal centers in secondary follicles. (From Abbas A, Lichtman A. Basic Immunology Updated Edition. 3rd ed. Philadelphia: Elsevier; 2010.)
Flow Through a Lymph Node
Afferent lymphatic vessel → subcapsular sinus → trabecular sinus → medullary sinus (filtration by macrophages) → efferent lymphatic vessel.
Medulla: The medulla of the node consists primarily of cords (densely packed lymphocytes) and sinuses (reticular cells and macrophages/histiocytes).
Paracortex: The area in the deep cortex containing the high endothelial venules where both B and T cells enter from the blood. T cells are concentrated within the paracortex; hence, when a cellular adaptive immune response occurs (T cell mediated), the paracortex enlarges.
Cortex: The area where B cells migrate and arrange in follicles. The primary follicles are densely packed and dormant, whereas the secondary follicles (after activation by antigen response) are large and have pale germinal centers.
The spleen is a critical component of the reticuloendothelial system in hematology and immunology. The spleen is structurally and functionally divided into two “pulp” divisions. The red pulp contains long vascular channels and a fenestrated basement membrane allowing for filtration of red blood cells (RBCs). Older senescent RBCs are filtered into the sinusoids but are unable to reenter the circulation and are phagocytosed by splenic macrophages. The white pulp contains the periarterial lymphatic sheath (PALS), which contains T cells and follicles that contain B cells.
Remember some of the findings after a splenectomy. Modest thrombocytosis (the spleen can store one third of total body platelets, so removal allows more to circulate in the blood), Howell-Jolly bodies (nuclear remnants in RBCs), poorer response to some vaccines, and higher risk for infection by encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Salmonella—“SHiNS”).
OVERVIEW OF INNATE VERSUS ADAPTIVE IMMUNITY
Basic Versus Learned Responses
The innate immune system (Figs. 6-2 and 6-3) is characterized by its fast and nonspecific response to infection as well as its lack of immune memory. It allows for an individual to have basic immunity before developing adaptive immunity (have a “baseline” immune system before learning to fight specific pathogens that are encountered). The innate immune system recognizes foreign antigens that are highly conserved over time and across pathogenic species. For example, lipopolysaccharide (LPS) is a component of the cell wall conserved between gram-negative bacteria. Toll-like receptors are able to recognize LPS and, once bound, activate the release of inflammatory cytokines.
Figure 6-2 The innate immune system has a fast and nonspecific response to infection. The adaptive immune system has a slower initial response, but a robust and specific response during subsequent exposures. (From Abbas A, Lichtman A. Basic Immunology Updated Edition. 3rd ed. Philadelphia: Elsevier; 2010.)
Figure 6-3 Comparison between innate immunity and adaptive immunity. (From Abbas A, Lichtman A. Basic Immunology Updated Edition. 3rd ed. Philadelphia: Elsevier; 2010.)
Constituents of innate immunity include phagocytes (neutrophils, macrophages, dendritic cells), natural killer (NK) cells, and the complement system. Epithelial barriers also prevent microbes from ever entering the body and are considered part of the innate immune system.
The adaptive immune system (see Figs. 6-2 and 6-3) is characterized by its slow initial response to a first-time antigen exposure and a more rapid and robust response during subsequent exposures secondary to “immune memory.” The adaptive immune system is able to generate a large diversity of antigen-specific responses. The adaptive immune system can be further divided into humoral immunity (circulating antibodies) and cell-mediated immunity (Fig. 6-4).
CELLS OF THE IMMUNE SYSTEM
Workhorses of Immunity
To begin, we’ll start with an overview of the various lineages that give rise to the cell types of the immune system. The cells of the immune system all originate from hematopoietic stem cells found within the marrow of long tubular bones. These hematopoietic stem cells are multipotent (can form all blood cell types) and have the capacity of self-renewal. These cells will differentiate to commit a cell down the path of either myeloid or lymphoid cell lines (see Chapter 11 for details).
Myeloid Lineage
Monocyte: Phagocytic cells located in the bloodstream that will differentiate into tissue macrophages once stimulated.
Macrophage: Tissue histiocyte (differentiated monocyte) capable of phagocytosis and synthesis and secretion of various cytokines (e.g., interleukin-1 [IL-1], tumor necrosis factor-α [TNF-α], IL-6, IL-8, and IL-12).
Dendritic cell: Cell with long cytoplasmic arms capable of efficient antigen presentation to lymphocytes (“professional antigen-presenting cell [APC]”).
Neutrophil: Mature cell that has a multilobed nucleus and contains toxic cytoplasmic granules with potent bactericidal capability.
Eosinophil: Mature cell that has a bilobed nucleus with large pink granules containing major basic protein. Major basic protein functions in attack against parasitic and helminthic infections.
Basophil: Mature cell that has a bilobed nucleus with large blue granules.
Mast cell: Cell with a small nucleus and large cytoplasmic granules containing histamine and other preformed allergic mediators, which play a role in allergies, hives, and anaphylaxis.
MAJOR HISTOCOMPATIBILITY COMPLEX I AND II
How We Differentiate Ourselves from Everything Else
The MHC is a critical portion of the immune system’s ability to discern self from nonself as well as detect when the body’s own cells are either infected or have undergone malignant change. There are two major classes of MHC involved in the human immune system; these two classes are both structurally and functionally distinct from one another (Fig. 6-5).
Figure 6-5 Comparison of MHC I versus MHC II. (From Abbas A, Lichtman A. Basic Immunology Updated Edition. 3rd ed. Philadelphia: Elsevier; 2010.)
MHC class I is present on all nucleated cells in the body and is encoded by human leukocyte antigen genes HLA-A, HLA-B, and HLA-C (Table 6-1). MHC is a cell surface protein that displays peptide fragments from inside the cell on the outside. Functionally, antigen is loaded onto the MHC I in the rough endoplasmic reticulum before the MHC I is inserted into the cell membrane. Normally the antigen that is loaded onto MHC I is self-antigen, and cytotoxic T cells (CD8 + T cells) will not react to it. If a virus infects a cell, however, the virus produces viral proteins using the host’s cellular machinery. These viral proteins will also be loaded onto MHC I. This is how cytotoxic T cells confer immunity to viral infection. They recognize MHC I with loaded viral antigen and targets it for cytotoxic destruction if the proper costimulatory signal is present (discussed later).
Table 6-1
Specific Diseases with an HLA Subtype Association
| Hla Subtype* | Associated Disease(S) |
| A3 | Hemochromatosis |
| B27 | Psoriasis, ankylosing spondylitis, inflammatory bowel disease, reactive arthritis (PAIR) |
| B8 | Graves disease |
| DR2 | Goodpasture disease |
| DR3 | Diabetes mellitus type 1 |
| DR4 | Diabetes mellitus type 1, rheumatoid arthritis |
| DR5 | Hashimoto thyroiditis, pernicious anemia |
*Certain HLA subtypes are linked with autoimmune disease. These associations are occasionally tested on Step 1.
MHC class II is present only on antigen-presenting cells such as macrophages and dendritic cells. It is encoded by human leukocyte antigen genes HLA-DP, HLA-DQ, and HLA-DR. Structurally, it is composed of two α- and two β-subunits. After APCs phagocytose microbes, they process and load these antigens onto MHC II. Then the MHC II is inserted into the cell membrane for binding and recognition by helper T cells (CD4 + T cells). Helper T cells can then activate B cells and/or trigger local inflammation.
B CELLS, ANTIBODIES, AND HUMORAL IMMUNITY
B Cell Is King
Humoral immunity is responsible for synthesizing soluble serum proteins called antibodies (or immunoglobulins), which have a variety of functions involved in eradicating infectious agents. Antibodies are composed of two light chains and two heavy chains that form a Y-shape. The trunk of the “Y” is the constant fragment (Fc) and the two branches are antigen-binding fragments (Fab) (Fig. 6-6). The chains are linked together by disulfide bonds. The Fc region is the constant region (containing the carboxy terminal and various carbohydrate side chains) and is important in both complement factor binding and determining the isotype of the immunoglobulin (e.g., immunoglobulin M [IgM], IgG, IgA, IgE, or IgD). The Fab region contains two antigen-binding fragments (at the amino terminal side) that are important in determining the idiotype of the immunoglobulin (uniqueness of the site and specificity for only one antigen).
Figure 6-6 The structure of an antibody. The antigen-binding region (Fab) is on the left of the diagram. The constant region (Fc) is on the right. Note that the antibody is composed of two light chains and two heavy chains connected by disulfide bonds (shown in red). (From Male D, Brostoff J, Roth D, Roitt I. Immunology. 7th ed. Philadelphia: Elsevier; 2007.)
Antibody formation is accomplished by mature plasma B cells, which synthesize and release antibodies after they have been activated by appropriate mechanisms following antigen stimulation. There are nearly unlimited antigens; therefore, there are a number of mechanisms in place to ensure that there will be a B cell that can make the required antibody when needed. This process is called antibody diversity and consists of four main processes:
1. Random recombination of VJ (light chain) or V(D)J (heavy chain) genes
2. Random combination of various heavy chains with light chains
3. Somatic hypermutation (in germinal centers following antigen stimulation)
4. TdT addition of DNA nucleotides to the heavy and light chains
At baseline, a mature B cell will either express IgM or IgD isotypes on its cell surface. Isotype switching occurs after antigen stimulation and appropriate activation of a mature B cell, resulting in alternative splicing of mRNA. The resultant post-translational modification of messenger RNA (mRNA) dictates the isotype of plasma cell (i.e., IgA, IgE, or IgG).
IgD: Found on the cell surface of mature B cells. Otherwise unclear function as a serum immunoglobulin.
IgM: Also found on the surface of mature B cells. As a serum immunoglobulin, it is produced in the primary (fast) antigenic response and is found as either a monomer or more commonly as a pentamer (five IgM molecules linked) for more efficient antigen trapping and complement fixation/activation. The pentamer is very bulky and therefore doesnot cross the placenta!
IgG: The main immunoglobulin in the secondary (delayed/slow) antigenic response. Occurs as a monomer with functions to fix complement, cross the placenta to provide passive immunity to a developing fetus, opsonize bacteria, and neutralize various toxins and viruses. IgG does not make multimers and therefore does cross the placenta!
IgA: Occurs as a monomer in the bloodstream and as a dimer when secreted (linked by the secretory component attained from epithelial cells before secretion). IgA is secreted onto mucosal surfaces (gastrointestinal, genitourinary, and respiratory) to block attachment of pathogens to mucous membranes.
IgE: Implicated in the allergic response (type 1 hypersensitivity) because it binds both mast cells and basophils and undergoes cross-linking after exposure to appropriate antigen.
Now, how does the B cell become activated and become an antibody secreting plasma cell? Resting B cells have a high level of expression of surface immunoglobulin (IgM or IgD) and MHC II, but they do not secrete immunoglobulin. If they encounter their matching antigen, they will engulf it, digest it, and present it on their MHC II. A helper T cell subtype 2 (Th2 cell) can then recognize the antigen on the MHC II with its T cell receptor (TCR). The Th2 cell will then secrete specific cytokines (IL-4, IL-5, and IL-6) to stimulate B cell proliferation, hypermutation, and isotype switching. Once a B cell becomes a plasma cell, it is no longer able to proliferate because it is designed for maximal immunoglobulin secretion. Of note, it actually takes two signals to make a Th2 cell secrete B cell activating cytokines: (1) the TCR–MHC II antigen interaction, and (2) CD40–CD40 ligand interaction.
There is also a T cell–independent way to activate B cells. Nonpeptide antigens cannot be presented to T cells, but it is often important for the immune system to recognize these antigens. B cells response to these antigens is solely IgM release. No isotype switching or immunologic memory is established after the encounter.
Active and Passive Immunity
The way that a host develops or obtains antibodies to a specific antigen can also be classified as active or passive immunity, both of which can be further subcategorized.
Active Immunity signifies that the host’s immune system came directly in contact with an antigen and developed its own immunity. There is a subcategorical breakdown of active immunity into naturally acquired active immunity (i.e., direct pathogen exposure) and artificially acquired active immunity (i.e., exposure through vaccination).
Passive Immunity occurs when the host was given its supply of antibodies by an outside source. This can also be naturally or artificially acquired. Naturally acquired passive immunity occurs most commonly when a mother transfers her actively formed antibodies to her offspring both transplacentally (IgG) and through breast milk (IgA). In contrast, artificially acquired passive immunity occurs when antibodies are administered as medication, which is the case in tetanus antitoxin, antivenoms, digitalis antibody fragments, or intravenous immunoglobulin (IVIG).
B Cell Deficiency and Immunoglobulin Deficiency Syndromes
X-linked agammaglobulinemia (Bruton agammaglobulinemia): Results from a mutation in the receptor tyrosine kinase (BTK).
Common variable immunodeficiency: Most common form of primary B cell deficiency with characteristically low levels of measureable IgG and IgA (occasionally IgM) resulting in immunodeficiency; associated with higher rates of lymphomas and gastric cancer.
Hyper IgM syndrome: Normal level of B cells but with diminished levels of IgG and IgA and with high levels of IgM; associated with higher risk for Pneumocystis infection. This condition usually results from an inability to undergo isotype class switching secondary to deficiency in CD40 ligand on Th2 cells.
Selective IgA deficiency: Most common immunoglobulin deficiency; associated with increased respiratory, gastrointestinal, and genitourinary infections. Associated with risk for anaphylaxis with blood product transfusions.
T CELLS, CELL-MEDIATED IMMUNITY, IMMUNE SYSTEM REGULATION
Regulators and Educated Assassins
T cells are critical in regulation, activation, and action of the adaptive immune system. As previously discussed, the T cells stem from the lymphoid lineage of hematopoietic differentiation. They are “born” in the bone marrow but “educated” in the thymus. Within the thymus both positive and negative selection occurs, resulting in specialized T cells with different clusters of differentiation (CD) on their cell surface; the main cell types are CD4 + and CD8 + T cells.
CD4 + T Cells
These “helper T cells” will undergo further differentiation after appropriate stimulation by interleukins to become either Th1 or Th2 cells with specific functions to help regulate both the humoral and cell-mediated immune system.
Th1: These cells are involved in the regulation of the cell-mediated response. They are activated by APCs and secrete interferon-γ (IFN-γ), which activates APCs for efficient killing. They also secrete IL-2, which activates CD8 + (cytotoxic T cells) to kill virally infected cells.
Th2: These cells are involved in activating B cells and enhance isotype switching by secreting IL-4, IL-5, and IL-6.
CD8 + T Cell
Otherwise known as cytotoxic T cells, these cells are responsible for seeking out and eliminating virus/parasite-infected cells, cancer cells, and other foreign cells.
It is important to understand the main steps involved when viral antigen is taken up by an APC to the point at which CD8 + T cells are “seeking and destroying” the infected cells.
1. When an APC (mainly dendritic cell or macrophage) is exposed to viral antigen, it will load the antigen onto an MHC II for presentation to a CD4 + T cell. It will also express a costimulatory signal on its cell membrane (e.g., B7). The TCR can then interact with the antigen-positive MHC II on the APC.
2. A single signal is not enough for activation. The immune system’s checks and balances require a second signal for appropriate activation to occur. The B7 costimulatory signal on the APC must interact with CD28 on the CD4 + T cell while the TCR–MHC II interaction is occurring. If these conditions are met, the CD4+ T cell will release IFN-γ to stimulate the APC to efficiently kill its pathogen. The CD4 + T cell will also release IL-2 to (1) cause activation and proliferation of CD8 + cytotoxic T cells to kill virally infected host cells and (2) cause CD4 + T cell proliferation and differentiation in an autocrine manner (Fig. 6-7).
Figure 6-7 Top row, A resting APC will not stimulate a CD4+ T cell even if the T cell receptor (TCR) binds MHC II. In fact, this causes anergy in the T cell to prevent autoimmune disease. Bottom row, B7 acts as a costimulatory signal that binds CD28 on the CD4+ T cell while the TCR–MHC II interaction is occurring. Now the T cell will be activated. It will secrete IL-2 to cause activation and proliferation of itself, and CD8+ cytotoxic T cells. (From Abbas A, Lichtman A. Basic Immunology Updated Edition. 3rd ed. Philadelphia: Elsevier; 2010.)
3. What happens when a TCR recognizes and binds to host antigens (self-reactivity)? In health, the way the immune system tackles this issue is by anergy, deactivating that self-reactive T cell. If this process fails, it could potentially lead to the development of an autoimmune disease.
High-Yield Cytokines/Interleukins
IL-1: An acute phase reactant synthesized by macrophages contributing to the acute inflammatory response, including fever, leukocyte recruitment, adhesion molecule activation, and stimulation of further chemokine production.
IL-2: Interleukin secreted by Th cells that enables growth, maturation, and proliferation of CD4 + and CD8 + T cells.
IL-3: Interleukin that stimulates bone marrow.
IL-4: Interleukin secreted by Th2 cells to further B cell development as well as enhance immunoglobulin class type switching to IgG.
IL-5: Interleukin secreted by Th2 cells that enhances immunoglobulin class type switching to IgE and increases production of eosinophils.
IL-6: Like IL-1, an acute phase reactant produced by Th cells and macrophages to further the acute inflammatory response. Also stimulates antibody production.
IL-8: Neutrophil chemotactic factor.
IL-10: Secreted by regulatory T cells in order to suppress cell-mediated immunity and stimulate humoral immunity.
IL-12: Secreted by macrophages with functions to enhance NK cells and T cells.
T Cell Deficiency Syndromes
Severe combined immunodeficiency (SCID): The most common form is X-linked SCID, followed by adenosine deaminase deficiency; results in susceptibility to numerous pathogenic infectious diseases (e.g., diarrhea, pneumonia, otitis, sinusitis).
Acquired immunodeficiency syndrome (AIDS): The final stage in the decremental quantity and quality of T cell immunity (particularly CD4 + cells); caused by infection with human immunodeficiency virus (HIV).
DiGeorge Syndrome: 22q11.2 deletion syndrome resulting in CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia).
Ataxia telangiectasia: T cell deficiency along with ataxia (cerebellar dysfunction) and increased risk for various cancer types (impaired double-stranded DNA repair).
COMPLEMENT SYSTEM
The Confusing Cascade of Complement Simplified
Complement is a system of liver-derived serum proteins that, once activated, triggers a cascade of proteolytic cleavage reactions to further the cascade and convert pro-proteins into functionally active immune system constituents. There are three main initial pathways that may be taken to ultimately activate C5 and initiate the final common pathway—the formation of the membrane attack complex (MAC) (Fig. 6-8).
Figure 6-8 The complement system and the formation of the membrane attack complex. (From Male D, Brostoff J, Roth D, Roitt I. Immunology. 7th ed. Philadelphia: Elsevier; 2007.)
Complement Deficiencies and Associated Conditions:
C1 esterase inhibitor deficiency → hereditary angioedema
Decay-accelerating factor (CD55) deficiency → paroxysmal nocturnal hemoglobinuria
Protectin (CD59) → paroxysmal nocturnal hemoglobinuria
C3 deficiency → propensity to develop severe, recurrent pyogenic infections of the sinus and respiratory tracts
HYPERSENSITIVITY RESPONSE
Immunity Gone Wild!
Type I (Allergy)
Type I reactions occur when presensitized mast cells or basophils with antigen-specific IgE are exposed to a particular antigen. The antigen binds the Fab portion of IgE, resulting in cross-linking and subsequent immediate release of preformed vasoactive substances (e.g., histamine). Anaphylactic reactions occur in this fashion through a type I reaction resulting in fast and widespread vasodilation and subsequent shock (hypotension). Bee stings and peanuts are common causes of anaphylaxis.
Type II (Antibody-Dependent Cytotoxic)
Type II reactions occur when either IgM or IgG antibodies bind to a cell surface antigen, resulting in cytotoxic destruction by a few possible mechanisms. These mechanisms include opsonization for histiocytes/neutrophils, activation of complement, and interference of cellular functioning.
Disorders: Autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), acute transfusion reactions with hemolysis, rheumatic fever, Goodpasture syndrome, bullous pemphigoid, pemphigus vulgaris, Graves disease, and myasthenia gravis.
Testing: Examples include the direct and indirect Coombs test of RBCs for hemolytic anemia and direct immunofluorescence of the glomerular basement membrane for Goodpasture syndrome (see Chapter 15).
Type III (Immune Complex Disease)
Type III reactions occur when antigen–antibody (mainly IgG) complexes form and are deposited in tissues, resulting in activation of the complement system and recruitment of neutrophils and leading to tissue injury. Historically, the Arthus reaction resulted from intradermal injection of antigen, which resulted in a type III reaction in the underlying skin, causing edema and necrosis.
Type IV (Delayed-Type Hypersensitivity, Antibody-Independent Cytotoxicity)
Type IV reactions are the only hypersensitivity reactions that are not antibody mediated and thus cannot be transferred through serum. These cell-mediated reactions occur in a delayed fashion after a previously exposed T lymphocyte interacts with the same antigen, resulting in lymphokine production and subsequent activation of other immune system players (e.g., macrophages).
Disorders: Contact dermatitis (e.g., nickel allergy, exposure to urushiol oil from poison ivy/oak), Mantoux skin test (PPD) for tuberculosis (TB) testing, graft-versus-host disease (GVHD), multiple sclerosis (MS), and Guillain-Barré syndrome.
Testing: The main clinical test utilizing the type IV response as a tool to help diagnose exposure to TB is the PPD test.
TRANSPLANTATION IMMUNOLOGY
Immunology is a critical factor whenever transplanting material with foreign antigens into a patient, whether it is a blood transfusion, a bone marrow transplant, or a solid organ transplant.
Types of Tissue Transplants
Autograft: Transplantation of tissue back to the same host in a different location. A common example would be skin grafting from one site to another.
Allograft: Transplantation of tissue from one human to another, such as is commonly performed in solid organ transplantation (e.g., kidney, liver, lung).
Xenograft: Tissue transplantation from a different animal species to a human.
Types of Rejection
Hyperacute rejection: Very rapid form of rejection occurring within minutes to hours of transplantation as a result of host antibodies binding to donor tissue endothelium. This results in complement activation and neutrophil migration into the donor graft.
Acute rejection: T cell–mediated rejection occurring within weeks to months after transplantation. This is the primary form of rejection for which immunosuppressant medications are used. This is the only form of rejection that can be acutely reversed by increased immunosuppressant dosing.
Chronic rejection: A long-term form of rejection in which there is progressive loss of function of the transplanted organ or tissue secondary to vascular fibrosis.
High-Yield Immunosuppressant Drugs
Azathioprine: A prodrug converted enzymatically in vivo to 6-mercaptopurine (6-MP), which acts to inhibit purine metabolism. Inhibition of purine metabolism preferentially affects proliferating cells such as T and B cells. Used both in autoimmune disorders and in acute rejection.
Cyclosporine: Binds to cyclophilin, which inhibits calcineurin and therefore prevents transcription of IL-2 in T lymphocytes. Used primarily in tissue transplantation.
Tacrolimus: Binds to FK-binding protein, but otherwise inhibits calcineurin (and therefore IL-2) similarly to cyclosporine. Used primarily as an alternative to cyclosporine in renal and liver transplant recipients.
Mycophenolate mofetil: Inhibits inosine monophosphate dehydrogenase, which is the rate-limiting enzyme in guanosine monophosphate (GMP) synthesis in the de novo purine synthesis pathway (see Chapter 2). Inhibition of purine synthesis inhibits replication of T and B cells. Primarily used in renal, heart, and liver transplant recipients.