Immune-mediated Diseases

Immune responses against pathogens are divided into the innate and adaptive immune response systems. The adaptive immune response, also called the acquired immune system, consists of 2 main mechanisms: the humoral- and cellular-mediated immune responses. Humoral immunity is mediated through B cells (producing antibodies), whereas cell-mediated immunity involves T cells, and this response is activated when the innate immune system fails to control an infection. As the 2nd line of defense, the adaptive immune system is slower and responds over a longer period of time, but the effect generally leads to specific immunological memory. The 2 important characteristics of adaptive response are specificity (with antigen recognition) and memory (immune response mounted with reinfection).

Type II hypersensitivity, also known as antibody-mediated cytotoxic hypersensitivity, is caused by immunoglobulin G (IgG) and IgM antibodies directed against antigens on cells or extracellular materials. The reaction leads to cytotoxic processes involving antibodies and the complement system. Interference with the normal cellular operation generating either stimulatory or inhibitory dysfunction is another mechanism that occurs. The inciting antigen can be intrinsic or part of the host cell. Extrinsic antigens such as blood products or medications can provoke a similar reaction. For diagnosis, laboratory tests and invasive procedures are utilized, depending on the system affected. Management of resulting disease ranges from supportive care to antibiotics, immunosuppressive medications, and surgery.

Type III hypersensitivity, also known as immune complex-mediated hypersensitivity, occurs when antibodies and antigens form immune complexes (ICs) in circulation and deposit in susceptible tissues. The complement system triggers the immune response, leading to leukocyte recruitment and tissue injury. There is no single clinical syndrome for this hypersensitivity. Symptoms reflect the impairment of multiple organ systems based on sites of IC deposition. Diagnostic workup depends largely on the history and includes laboratory tests, imaging, and biopsy of the affected organ. Treatment consists of removal or avoidance of offending agents and, in severe conditions, glucocorticoids or immunosuppressive therapy.

Type IV hypersensitivity reaction, or delayed-type hypersensitivity, is a cell-mediated response to antigen exposure. The reaction involves T cells, not antibodies, and develops over several days. Presensitized T cells initiate the immune defense, leading to tissue damage. A cytokine-mediated process is activated by T-helper cells while cytotoxic T cells directly release cytotoxins to infected or dysfunctional cells, causing cell lysis. Clinical manifestations depend on the system involved, so diagnostic tests rely on history and findings. Treatment includes controlling the effects of the immune response with glucocorticoids and immunosuppressive therapy while managing the associated disease complications.

B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. The process entails antigen stimulation, with or without the help of T cells. The T-cell–independent activation generates a short-lived immune response (via plasma cells), and this is seen with antigens such as bacterial lipopolysaccharides. T-cell–dependent activation, on the other hand, produces both plasma cells and memory cells. Activated B cells then proliferate in the germinal centers, but not all become effector B cells. Through somatic hypermutation, B cells undergo additional mechanisms to increase the affinity of the antibody to the antigen. Only those with high-affinity B-cell receptors subsequently advance for terminal differentiation. B cells then go through class switching (from IgM to another class of Ig) under the influence of cytokines. After class switching, the B cells become plasma cells (which produce antibodies) or memory cells (which mount a robust secondary immune response).

Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins underlie the development and differentiation of T and B lymphocytes and hematopoietic cells.

T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. A functional mature T cell develops from a step-by-step process creating a T-cell receptor (TCR) complex, selecting T cells with appropriate affinity to self-antigens associated with major histocompatibility molecules (positive selection), and expressing either CD4 or CD8. In this series, cells predisposed to autoimmunity undergo apoptosis (negative selection). When released from the thymus, the naive mature T cells travel to the secondary lymphoid organs for activation. Two signals, an antigen-specific binding of TCR and costimulation, are required to be activated (ready to mount an immune response). In the case of CD8+ T cells, additional cytokine stimulation is necessary. Depending on the cytokines they are exposed to during antigen stimulation, the undifferentiated mature T cell (Th0) develops into cells with different functions: CD4+ become T helper (Th) cells and CD8+ become cytotoxic, or cytolytic, cells. Th cells have other subtypes; the most characterized are Th1, Th2, Th17, follicular Th cells, and regulatory T cells. Other types include natural killer T cells and memory T cells. These mature differentiated T cells ensure effective surveillance and immediate response to pathogens, tumor cells, and foreign tissues and provide immunologic memory.

Immunity to pathogens is divided into innate and adaptive immune responses. The innate immune response is the 1st line of defense against a variety of pathogens, including bacteria, fungi, viruses, and parasites. In essentially the same form, the innate type of immunity is present in all multicellular organisms. The innate immune response is activated within minutes to hours after exposure to an infection, which curtails microbe invasion at the initial stages. The pathogen has specific components recognized by pattern recognition receptors (PRRs). After identification of a microbial invasion, noncellular components (including the complement system and cytokines) act in concert with cellular elements to achieve cell recruitment, direct microbial killing, or phagocytosis induction. The steps all aim to eliminate the pathogen. Antimicrobial mechanisms in phagocytosis include acidification and respiratory/oxidative burst. The process terminates with destruction of the threat while maintaining immunologic homeostasis. The defense is also important in activating the adaptive immune system.

Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor necrosis factor interacts with 2 receptors, which initiate signal transduction pathways leading to different cellular responses (inflammation, cell survival, or apoptosis). Inappropriate or unrestrained activation of TNF signaling produces chronic inflammation, as seen in autoimmune conditions (e.g., rheumatoid arthritis, psoriasis). The mechanism of TNF inhibition has been used in treating these inflammatory diseases.

Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. Antibodies undergo processes that improve antigen affinity and provide appropriate defense by class switching. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. General functions include opsonization, neutralization of infectivity of the pathogens, cytotoxicity, and complement activation. Specific classes have unique defensive mechanisms.

Cell-mediated immunity is an integral part of the adaptive immune system, mounting a highly specific defense against pathogens. Cell-mediated immunity develops over a longer period of time than innate immunity. Cell-mediated adaptive response occurs in cells/tissues (intracellular infections or aberrant cells (e.g., tumors)) and involves the T cells or T lymphocytes. The cells, which arise from bone marrow, migrate to the thymus for further maturation. A T cell receptor is assembled and activation is facilitated by antigen-presenting cells in secondary lymphoid organs. Influenced by cytokines, activated T cells can differentiate into subsets (e.g., CD4+ T helper cells, CD8+ cytotoxic T cells, memory T cells). T helper cells aid in the eradication of pathogens by helping the partners of immune cells (e.g., macrophages and granulocytes). With mechanisms activating the caspase pathway, cytotoxic T cells have the capacity to kill microbes. Memory T cells develop after initial exposure to the antigen and become effector T cells on reinfection. T cells also activate B cells (a major component in humoral immunity), which enhance the ability to eliminate pathogens.

Humoral adaptive immunity is an integral part of the adaptive immune system, which mounts a highly specific defense against pathogens but takes a longer time to respond (compared to the innate immune system). Humoral immunity is the arm of the immune system protecting the extracellular fluids of the lymphatics (lymph), interstitium, and circulatory system (plasma) from microbial contamination mediated through soluble molecules. The B cells play a major role, producing antibodies or immunoglobulins. Arising from the bone marrow, B cells originate from the common lymphoid progenitor and undergo stages to assemble the B cell receptor. To become fully functional, activation follows, and this can be T cell–dependent (which produces memory cells) or T cell–independent (producing a short-lived response). When activated, B cells go through processes enhancing antigen affinity, class switching, and differentiation to plasma cells and memory cells. Plasma cells produce the antibodies, while memory B cells respond to reinfection. There are different immunoglobulin isotypes, generally providing immune protection through complement activation, opsonization, neutralization of toxins or viruses, and induction of cell lysis.

The immune system is equipped with a varied repertoire of defense mechanisms against pathogens. Functionally, the immune system is differentiated into the innate and adaptive components. Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins (e.g., complement) that relay signals of a threat, and immune cells that help eliminate the microbe. Pathogen-associated molecular patterns (PAMPs) in microorganisms and damage-associated molecular patterns (DAMPs) from injured tissues are identified, and the appropriate cells are recruited. Involved cells include phagocytes and accessory cells. The offending pathogens are engulfed by phagocytes for destruction. In antigen-presenting cells (the most potent of which is the dendritic cell), parts of the pathogen material or peptides are transported to the cell surface. Through a unique antigen-loading mechanism specific to MHC I or II, the processed antigen peptides are then presented to the appropriate T cells, leading to T-cell activation. This interaction links innate immunity with adaptive immunity.

Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. These conditions are more commonly seen in women. Autoimmune diseases are chronic, with clinical manifestations consistent with the associated immune response. Among these conditions are Graves’ disease (autoantibodies against thyroid hormone receptors), myasthenia gravis (antibodies against acetylcholine receptors), type 1 diabetes (pancreatic β-cell destruction by immune cells), and systemic lupus erythematosus (multiorgan damage driven by immune complexes and autoantibodies).

Type I hypersensitivity reaction is an abnormal immune response triggered by exposure to specific antigens known as allergens. In this type of hypersensitivity reaction, the presentation of the antigen to the T-helper cells (Th cells) initiates a cascade of immunologic events leading to the production of antigen-specific IgE antibodies. Reexposure to the antigen promotes degranulation of the IgE-bound mast cells and basophils, releasing chemical mediators that cause various allergy symptoms. Manifestations can be local, depending on the route of entry of the antigen. In severe cases, systemic reaction leads to anaphylactic shock. To determine allergic etiology, skin testing as well as in vitro tests are available. Management includes avoidance of triggers to reduce exacerbation. Common treatment options are antihistamines and glucocorticoids to control the inflammatory response. Anaphylaxis, however, is a medical emergency that requires immediate airway access with administration of epinephrine and fluid resuscitation.