Treatments used to combat autoimmune diseases and conditions caused by eosinophils include:

- corticosteroids – promote apoptosis. Numbers of eosinophils in blood are rapidly reduced

- monoclonal antibody therapy – e.g., mepolizumab or reslizumab against IL-5, prevents eosinophilopoiesis

- antagonists of leukotriene synthesis or receptors

- imatinib (STI571) – inhibits PDGF-BB in hypereosinophilic leukemia

Monoclonal antibodies such as dupilumab and lebrikizumab target IL-13 and its receptor, which reduces eosinophilic inflammation in pateints with asthma due to lowering the number of adhesion molecules present for eosinophils to bind to, thereby decreasing inflammation. Mepolizumab and benralizumab are other treatment options that target the alpha subunit of the IL-5 receptor, thereby inhibiting its function and reducing the number of developing eosinophils as well as the number of eosinophils leading to inflammation through antibody-dependent cell-mediated cytotoxicity and eosinophilic apoptosis.

In a large number of phase I and phase II studies, autologous and allogeneic CIK cells displayed a high cytotoxic potential against a broad range of varying tumor entities, whereas side effects were only minor. In many cases, CIK cell treatment led to complete remissions of tumor burden, prolonged survival durations and improved quality of life, even in advanced disease stages.

Currently, the utilization of CIK cell treatment is restricted to clinical studies, but this therapeutic approach might also benefit patients as first-line treatment modality in the future.

CIK cells, along with the administration of IL-2 have been experimentally used to treat cancer in mice and humans with low toxicity.

A T cell, or T lymphocyte, is a type of lymphocyte (a subtype of white blood cell) that plays a central role in cell-mediated immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface. They are called "T cells" because they mature in the thymus from thymocytes (although some also mature in the tonsils). The several subsets of T cells each have a distinct function. The majority of human T cells rearrange their alpha and beta chains on the cell receptor and are termed alpha beta T cells (αβ T cells) and are part of the adaptive immune system. Specialized gamma delta T cells, (a small minority of T cells in the human body, more frequent in ruminants), have invariant T-cell receptors with limited diversity, that can effectively present antigens to other T cells and are considered to be part of the innate immune system.

Monocytes are a type of "leukocyte", or white blood cell. They are the largest type of leukocyte and can differentiate into macrophages and myeloid lineage dendritic cells. As a part of the vertebrate innate immune system monocytes also influence the process of adaptive immunity. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors.

The category of effector T cell is a broad one that includes various T cell types that actively respond to a stimulus, such as co-stimulation. This includes helper, killer, regulatory, and potentially other T cell types.

Research into AM functionality has been on the rise since AMs are one of the first lines of a defense against invasive pathogens. One of the most prominent fields is investigating liposomes as deliverers of antibiotics for treatment of respiratory intracellular infections. Intracellular parasites, such as M. tuberculosis, C. pneumoniae, L. monocytogenes, L. pneumophila, and F. tularensis, (to name a few) are taken up by AMs via phagocytosis, but are resistant to the biocidal mechanisms of AMs and can survive intracellularly, thus inducing severe respiratory infections. Pulmonary tuberculosis is caused by M. tuberculosis, and is now a major infectious disease worldwide and its incidence is increasing, especially in association with the AIDS pandemic. For sterilization of intracellular parasites in AMs, antibiotics are normally given orally or intravenously, but much of the antibiotics disperse to many different tissues, diminishing its effectiveness. Pulmonary administration of mannosylated liposomes is a much more direct, efficient route in targeting AMs; it enhances antimicrobial effect, reduces the dosage needed, and avoids unnecessary distribution to the blood. Since mannose receptors are exclusively expressed on the surface of AM, mannosylation of liposomes is an appealing approach to cell-selective targeting to AM. The efficacy of pulmonary administration of ciprofloxacin (CPFX) incorporated into mannosylated liposomes (mannosylated CPFX-lipososomes) was examined in rats, and determined to be an efficient means to target AMs.

Plasma cells, also called plasma B cells, plasmocytes, plasmacytes, or effector B cells, are white blood cells that secrete large volumes of antibodies. They are transported by the blood plasma and the lymphatic system. Plasma cells originate in the bone marrow; B cells differentiate into plasma cells that produce antibody molecules closely modelled after the receptors of the precursor B cell. Once released into the blood and lymph, these antibody molecules bind to the target antigen (foreign substance) and initiate its neutralization or destruction.

The T helper cells (T cells) are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages.

Mature T cells express the surface protein CD4 and are referred to as CD4 T cells. Such CD4 T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an antigen-presenting cell expresses an antigen on MHC class II, a CD4 cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 (protein) and CD40L) and through cytokines.

CD154, also called CD40 ligand or CD40L, is a cell surface protein that mediates T cell helper function in a contact-dependent process and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. CD154 acts as a costimulatory molecule and is particularly important on a subset of T cells called T follicular helper cells (T cells). On T cells, CD154 promotes B cell maturation and function by engaging CD40 on the B cell surface and therefore facilitating cell-cell communication. A defect in this gene results in an inability to undergo immunoglobulin class switching and is associated with hyper IgM syndrome. Absence of CD154 also stops the formation of germinal centers and therefore prohibiting antibody affinity maturation, an important process in the adaptive immune system.

The importance of helper T cells can be seen from HIV, a virus that primarily infects CD4 T cells. In the advanced stages of HIV infection, loss of functional CD4 T cells leads to the symptomatic stage of infection known as the acquired immunodeficiency syndrome (AIDS). When the HIV virus is detected early in blood or other bodily fluids, continuous therapy can delay the time at which this fall happens. Therapy can also better manage the course of AIDS if and when it occurs. There are other rare disorders such as lymphocytopenia which result in the absence or dysfunction of CD4 T cells. These disorders produce similar symptoms, many of which are fatal.

Monocytes are amoeboid in appearance, and have agranulated cytoplasm. Containing unilobar nuclei, these cells are one of the types of mononuclear leukocytes which shelter azurophil granules. The archetypal geometry of the monocyte nucleus is ellipsoidal; metaphorically bean-shaped or kidney-shaped, although the most significant distinction is that the nuclear envelope should not be hyperbolically furcated into lobes. Contrast to this classification occurs in polymorphonuclear leukocytes. Monocytes compose 2% to 10% of all leukocytes in the human body and serve multiple roles in immune function. Such roles include: replenishing resident macrophages under normal conditions; migration within approximately 8–12 hours in response to inflammation signals from sites of infection in the tissues; and differentiation into macrophages or dendritic cells to effect an immune response. In an adult human, half of the monocytes are stored in the spleen. These change into macrophages after entering into appropriate tissue spaces, and can transform into foam cells in endothelium.

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigen (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines.

In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ. (The "B" from B cells comes from the name of this organ, where it was first discovered by Chang and Glick, and not from bone marrow as commonly believed).

B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane. BCRs allow the B cell to bind a specific antigen, against which it will initiate an antibody response.

Gamma delta T cells (γδ T cells) are T cells that have a distinctive T-cell receptor (TCR) on their surface. Most T cells are αβ (alpha beta) T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually much less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

The antigenic molecules that activate gamma delta T cells are still largely unknown. However, γδ T cells are peculiar in that they do not seem to require antigen processing and major-histocompatibility-complex (MHC) presentation of peptide epitopes, although some recognize MHC class Ib molecules. Furthermore, γδ T cells are believed to have a prominent role in recognition of lipid antigens. They are of an invariant nature and may be triggered by alarm signals, such as heat shock proteins (HSP).

There also exists a γδ-T-cell sub-population within the epidermal compartment of the skin of mice. Originally referred to as Thy-1+ dendritic epidermal cells (Thy1+DEC), these cells are more commonly known as dendritic epidermal T cells (DETC). DETCs arise during fetal development and express an invariant and canonical Vγ3 Vδ1 T-cell receptor [using Garman nomenclature].

An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called an eosinophilia, and is typically seen in people with a parasitic infestation of the intestines; autoimmune and collagen vascular disease (such as rheumatoid arthritis) and Systemic lupus erythematosus; malignant diseases such as eosinophilic leukemia, clonal hypereosinophilia, and Hodgkin's disease; lymphocyte-variant hypereosinophilia; extensive skin diseases (such as exfoliative dermatitis); Addison's disease and other causes of low corticosteroid production (corticosteroids suppress blood eosinophil levels); reflux esophagitis (in which eosinophils will be found in the squamous epithelium of the esophagus) and eosinophilic esophagitis; and with the use of certain drugs such as penicillin. But, perhaps the most common cause for eosinophilia is an allergic condition such as asthma. In 1989, contaminated L-tryptophan supplements caused a deadly form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the Toxic Oil Syndrome in Spain in 1981.

Eosinophils play an important role in asthma as the number of accumulated eosinophils corresponds to the severity of asthmatic reaction. Eosinophilia in mice models are shown to be associated with high interleukin-5 levels. Furthermore, mucosal bronchial biopsies conducted on patients with diseases such as asthma have been found to have higher levels of interleukin-5 leading to higher levels of eosinophils. The infiltration of eosinophils at these high concentrations causes an inflammatory reaction. This ultimately leads to airway remodelling and difficulty of breathing.

Eosinophils can also cause tissue damage in the lungs of asthmatic patients. High concentrations of eosinophil major basic protein and eosinophil-derived neurotoxin that approach cytotoxic levels are observed at degranulation sites in the lungs as well as in the asthmatic sputum.

Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to viral-infected cells, acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the initial notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor-generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus, where they then enter into the circulation. NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting interferon gamma. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice (including BALB/c mice) and in three common monkey species.

In addition to the knowledge that natural killer cells are effectors of innate immunity, recent research has uncovered information on both activating and inhibitory NK cell receptors which play important functional roles, including self tolerance and the sustaining of NK cell activity. NK cells also play a role in the adaptive immune response: numerous experiments have demonstrated their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory, fundamental for responding to secondary infections with the same antigen. The role of NK cells in both the innate and adaptive immune responses is becoming increasingly important in research using NK cell activity as a potential cancer therapy.

Since NK cells recognize target cells when they express nonself HLA antigens (but not self), autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all T cells be removed before infusion into the patients to remove the risk of graft versus host disease, which can be fatal. This can be achieved using an immunomagnetic column (CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few weeks and the yield is donor-dependent. A simpler way to obtain high numbers of pure NK cells is to expand NK-92 cells whose cells continuously grow in culture and can be expanded to clinical grade numbers in bags or bioreactors. Clinical studies have shown it to be well tolerated and some antitumor responses have been seen in patients with lung cancer, melanoma, and lymphoma.

Infusions of T cells engineered to express a chimeric antigen receptor that recognizes an antigen molecule on leukemia cells could induce remissions in patients with advanced leukemia. Logistical challenges are present for expanding T cells and investigators are working on applying the same technology to peripheral blood NK cells and NK-92.

In a study at Boston Children's Hospital, in coordination with Dana-Farber Cancer Institute, whereby immunocompromised mice had contracted lymphomas from EBV infection, an NK-activating receptor called NKG2D was fused with a stimulatory Fc portion of the EBV antibody. The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.

After leaving the bone marrow, the B cell acts as an antigen presenting cell (APC) and internalizes offending antigens, which are taken up by the B cell through receptor-mediated endocytosis and processed. Pieces of the antigen (which are now known as "antigenic peptides") are loaded onto MHC II molecules, and presented on its extracellular surface to CD4+ T cells (sometimes called "T helper cells"). These T cells bind to the MHC II-antigen molecule and cause activation of the B cell. This is a type of safeguard to the system, almost like a two-factor authentication method. First, the B cells have to encounter a foreign antigen, and are then required to be activated by T helper cells before they differentiate to specific cells.

Upon stimulation by a T cell, which usually occurs in germinal centers of secondary lymphoid organs like the spleen and lymph nodes, the activated B cell begins to differentiate into more specialized cells. Germinal center B cells may differentiate into memory B cells or plasma cells. Most of these B cells will become plasmablasts (or "immature plasma cells"), and eventually plasma cells, and begin producing large volumes of antibodies. Some B cells will undergo a process known as affinity maturation. This process favors, by selection for the ability to bind antigen with higher affinity, the activation and growth of B cell clones able to secrete antibodies of higher affinity for the antigen.

In terms of the management of T cell deficiency for those individuals with this condition the following can be applied:

- Killed vaccines should be used(not "live vaccines" in T cell deficiency)

- Bone marrow transplant

- Immunoglobulin replacement

- Antiviral therapy

- Supplemental nutrition

In the U.S. this defect occurs in about 1 in 70,000, with the majority of cases presenting in early life.

Furthermore, SCID has an incidence of approximately 1 in 66,000 in California

Apoptosis is one of the major mechanisms of cell death targeted by cancer therapies. Reduced susceptibility to apoptosis increases the resistance of cancer cells to radiation and cytotoxic agents. B-cell lymphoma-2 (Bcl-2) family members create a balance between pro and anti-apoptotic proteins. Pro-apoptotic proteins include Bax and Bak. Anti-apoptotic proteins include Bcl-2, Bcl-X, Bcl-w, Mcl-1. When anti-apoptotic family members are overexpressed, apoptotic cell death becomes less likely.

- Oblimersen sodium (G3139, Genasense) targets BCL-2 mRNA

- ABT-737 (oral form navitoclax, ABT-263). A small molecule that targets anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-X and Bcl-w). ABT-737 binds anti-apoptotic Bcl-2 proteins with an affinity two or three orders of magnitude more potent than previously reported compounds. High basal levels of Mcl-1 expression are associated with resistance to ABT-737. Combining ABT-737 with second agents that inactivate Mcl-1 may reduce this effect. ABT-737 has demonstrated single-agent efficacy against cell lines from lymphoid malignancies known to express high levels of Bcl-2, including DLBCL. It has also been found to be synergistic with proteasome inhibitors.

- Fenretinide. A synthetic retinoid that induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs by triggering the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak.

Monoclonal antibodies are made by injecting human cancer cells into mice so that their immune systems create antibodies against foreign antigens. Monoclonal antibodies target specific antigens on cancer cells and may enhance the patient's immune response. They can be administered alone or be linked (conjugated) to anticancer drugs, radioisotopes, or other biologic response modifiers. There are several therapeutic mechanisms for monoclonal antibodies:

1. Directly initiates apoptosis in the targeted cells

2. Antibody-dependent cell-mediated cytotoxicity (ADCC) -- Recruits monocytes, macrophages, and natural killer cells to destroy the targeted cells

3. Complement-dependent cytotoxicity (CDC)-- Initiates the complement system which activates the membrane attack complex causing cell lysis and death.

4. Delivers chemotherapy or radiation in a targeted manner which allows higher concentrations to be administered

Monoclonal antibodies for treatment of B-cell malignancies

- CD20. Approximately 95% of B-cell lymphomas express CD20, but CD20 is not critical for B-cell survival. Clonal B-cells spontaneously mutate the idiotypic region of their immunoglobulin. This high mutation rate makes them prone to the selection of B-cells lacking the CD20 antigen following treatment with CD20-targeting monoclonal antibodies. As a result, CD20 may lose its effectiveness as a target after as little as one or two treatments with monoclonal antibodies such as rituximab. A study in Japan found that approximately 26% of relapsed B-cell lymphoma patients lost CD20 expression during treatment with rituximab. Lab tests involving 5-Aza showed that CD20 expression and rituximab sensitivity could be restored in some cases using epigenetic drug treatment.

- Rituximab (Rituxan. The mechanism of action of Rituximab against DLBCL is not fully understood, but studies suggest that rituximab modulates cellular and molecular signal transduction pathways that regulate bcl-2-expression. Interaction between bcl-2 expression and IL-10 growth factors may contribute to the resistance mechanisms of DLBCL to chemotherapy.

- Tositumomab (Bexxar). Anti-CD20 conjugated with radionuclide iodine-131

- Ibritumomab tiuxetan (Zevalin). Anti-CD20 conjugated with radioactive isotope (either yttrium-90 or indium-111)

- CD22. Approximately 85% of DLBCLs express CD22. It is expressed on pre-B and mature B cells, and expression is lost upon maturation to plasma cells.

- Epratuzumab (Lymphocide). After binding epratuzumab, CD22 is rapidly internalized. Cell death does not appear to be mediated by complement, but modest antibody-dependent cellular cytotoxicity and direct killing effects have been demonstrated.

- CD70. In normal lymphoid tissues CD27 and its ligand CD70 have a restricted expression pattern, but a 1999 study found CD70 on 71% of large B-cell lymphomas.

- Vorsetuzumab mafodotin (antibody conjugated to monomethyl auristatin F). Monomethyl auristatin F is a mitotic inhibitor. Preliminary data from a phase I clinical trial of vorsetuzumab mafodotin showed that of the 7 patients with non-Hodgkin lymphoma, one achieved complete remission, four were stable, one experienced progressive disease, and one was not evaluable.

The immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a hypersensitivity response occurs. Hypersensitivity is believed to be the cause of allergy and some auto-immune disease.

Hypersensitivity reactions can be divided into four types:

- Type 1 hypersensitivity includes common immune disorders such as asthma, allergic rhinitis (hay fever), eczema, urticaria (hives) and anaphylaxis. These reactions all involve IgE antibodies, which require a T2 response during helper T cell development. Preventive treatments, such as corticosteroids and montelukast, focus on suppressing mast cells or other allergic cells; T cells do not play a primary role during the actual inflammatory response. It's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the T model.

- Type 2 and Type 3 hypersensitivity both involve complications from auto-immune or low affinity antibodies. In both of these reactions, T cells may play an accomplice role in generating these auto-specific antibodies, although some of these reactions under Type 2 hypersensitivity would be considered normal in a healthy immune system (for example, Rhesus factor reactions during child-birth is a normal immune response against child antigens). The understanding of the role of helper T cells in these responses is limited but it is generally thought that T2 cytokines would promote such disorders. For example, studies have suggested that lupus (SLE) and other auto-immune diseases of similar nature can be linked to the production of T2 cytokines.

- Type 4 hypersensitivity, also known as delayed type hypersensitivity, are caused via the over-stimulation of immune cells, commonly lymphocytes and macrophages, resulting in chronic inflammation and cytokine release. Antibodies do not play a direct role in this allergy type. T cells play an important role in this hypersensitivity, as they activate against the stimulus itself and promote the activation of other cells; particularly macrophages via T1 cytokines.

Other cellular hypersensitivities include cytotoxic T cell mediated auto-immune disease, and a similar phenomenon; transplant rejection. Helper T cells are required to fuel the development of these diseases. In order to create sufficient auto-reactive killer T cells, interleukin-2 must be produced, and this is supplied by CD4 T cells. CD4 T cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as interferon-gamma, encouraging these cytotoxic cells to kill host cells in certain circumstances.

The mechanism that killer T cells use during auto-immunity is almost identical to their response against viruses, and some viruses have been accused of causing auto-immune diseases such as Type 1 diabetes mellitus. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system believes, by mistake, that a host antigen is foreign. As a result, the CD8 T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.

Some of this section is a simplification. Many auto-immune diseases are more complex. A well-known example is rheumatoid arthritis, where both antibodies and immune cells are known to play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.

This table summarizes the nomenclature of mouse Vγ chains and indicates monoclonal antibodies often used to identify these chains. This system has been best described in strain C57BL/6 and might not apply well to other strains. There are two systems of nomenclature in use (Heilig; Garman), and many writers do not indicate which system they use. For example, the IMGT (International Immunogenetics Information System) uses the Heilig notation, but does not indicate this fact on its website. This table refers to variable chain Vγ gene segments and to monoclonal antibodies that detect the corresponding Vγ protein chains. Note that Adrian Hayday's proposed nomenclature is not widely used, leaving considerable confusion in the literature. One advantage and weakness of the Hayday nomenclature is that it is based on the gene order in the B6 genome, but this might not apply to other strains.

An alveolar macrophage (or dust cell) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall.

Activity of the alveolar macrophage is relatively high, because they are located at one of the major boundaries between the body and the outside world. They are responsible for removing particles such as dust or microorganisms from the respiratory surfaces.

Alveolar macrophages are frequently seen to contain granules of exogenous material such as particulate carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers.

Inhaled air may contain particles or organisms which would be pathogenic. The respiratory pathway is a prime site for exposure to pathogens and toxic substances. The respiratory tree, comprising the larynx, trachea, and bronchioles, is lined by ciliated epithelia cells that are continually exposed to harmful matter. When these offensive agents infiltrate the superficial barriers, the body's immune system responds in an orchestrated defense involving a litany of specialized cells which target the threat, neutralize it, and clean up the remnants of the battle.

Deep within the lungs exists its constituent alveoli sacs, the sites responsible for the uptake of oxygen and excretion of carbon dioxide. There are three major alveolar cell types in the alveolar wall (pneumocytes):

- Type I pneumocyte (Squamous Alveolar) cells that form the structure of an alveolar wall.

- Type II pneumocyte (Great Alveolar) cells that secrete pulmonary surfactant to lower the surface tension of water and allows the membrane to separate, thereby increasing the capability to exchange gases. Surfactant is continuously released by exocytosis. It forms an underlying aqueous protein-containing hypophase and an overlying phospholipid film composed primarily of dipalmitoyl phosphatidylcholine.

- Macrophages that destroy foreign material, such as bacteria.

Type 1 and type 2 pneumocytes. Type 1 pneumocytes (or membranous pneumocytes) form the structure of the alveolus and are responsible for the gas exchange in the alveolus. Type 1 pneumocytes are squamous epithelial cells which are characterized by a superficial layer consisting of large, thin, scale-like cells; they also cover 95% of the alveolar surface, although they are only half as numerous as Type 2 pneumocytes. Type 2 pneumocytes are important in that they can proliferate and differentiate into type 1 pneumocytes, which cannot replicate and are susceptible to a vast numbers of toxic insults. Type 2 pneumocytes are also important because they secrete pulmonary surfactant(PS), which consists 80–90% of phospholipids [(phosophatidylcholine(PC), phosphatidyglycerol(PG), phosphaditylinositol (PI)] and 5-10% of surfactant proteins (SP-A, SP-B, SP-C, AND SP-D). PS is synthesized as lamellar bodies, which are structures consisting of closely packed bilayers that are secreted and then undergo transformation into a morphological form called tubular myelin. PS plays an important role in maintaining normal respiratory mechanics by reducing alveolar surface tension. By lowering alveolar surface tension, PS reduces the energy required to inflate the lungs, and reduces the likelihood of alveolar collapse during expiration. Loosely attached to these alveoli sacs are the alveolar macrophages that protect the lungs from a broad array of microbes and aerosols by devouring and ingesting them through phagocytosis.

Alveolar macrophages are phagocytes that play a critical role in homeostasis, host defense, the response to foreign substances, and tissue remodeling. Since alveolar macrophages are pivotal regulators of local immunological homeostasis, their population density is decisive for the many processes of immunity in the lungs. They are highly adaptive components of the innate immune system and can be specifically modified to whatever functions needed depending on their state of differentiation and micro-environmental factors encountered. Alveolar macrophages release numerous secretory products and interact with other cells and molecules through the expression of several surface receptors. Alveolar macrophages are also involved in the phagocytosis of apoptotic and necrotic cells that have undergone cell-death. They must be selective of the material that is phagocytized because normal cells and structures of the body must not be compromised. To combat infection, the phagocytes of the innate immune system facilitates many pattern recognition receptors (PRR) to help recognize pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic microorganisms. PAMPs all have the common features of being unique to a group of pathogens but invariant in their basic structure; and are essential for pathogenicity(ability of an organism to produce an infectious disease in another organism). Proteins involved in microbial pattern recognition include mannose receptor, complement receptors, DC-SIGN, Toll-like receptors(TLRs), the scavenger receptor, CD14, and Mac-1. PRRs can be divided into three classes:

1. signaling PRRs that activate gene transcriptional mechanisms that lead to cellular activation,

2. endocytic PRRs that function in pathogen binding and phagocytosis, and

3. secreted PRRs that usually function as opsonins or activators of complement.

The recognition and clearance of invading microorganisms occurs through both opsonin-dependent and opsonin–independent pathways. The molecular mechanisms facilitating opsonin-dependent phagocytosis are different for specific opsonin/receptor pairs. For example, phagocytosis of IgG-opsonized pathogens occurs through the Fcγ receptors (FcγR), and involves phagocyte extensions around the microbe, resulting in the production of pro-inflammatory mediators. Conversely, complement receptor-mediated pathogen ingestion occurs without observable membrane extensions (particles just sink into the cell) and does not generally results in an inflammatory mediator response.

Following internalization, the microbe is enclosed in a vesicular phagosome which then undergoes fusion with primary or secondary lysosomes, forming a phagolysosome. There are various mechanisms that lead to intracellular killing; there are oxidative processes, and others independent of the oxidative metabolism. The former involves the activation of membrane enzyme systems that lead to a stimulation of oxygen uptake (known as the respiratory burst), and its reduction to reactive oxygen intermediates (ROIs), molecular species that are highly toxic for microorganisms. The enzyme responsible for the elicitation of the respiratory burst is known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is composed of five subunits. One component is a membrane cytochrome made up of two protein subunits, gp91phox and p22phox; the remaining three components are cytosolic-derived proteins: p40phox, p47phox, and p67phox. NADPH oxidase exists in the cytosol of the AM when in a quiescent state; but upon activation, two of its cytosolic components, p47phox and p67phox, have their tyrosine and serine residues phosphorylated, which are then able to mediate translocation of NADPHox to the cytochrome component, gp91phox/p22phox, on the plasma membrane via cytoskeletal elements.

Compared to other phagocytes, the respiratory burst in AM is of a greater magnitude. Oxygen-independent microbicidal mechanisms are based on the production of acid, on the secretion of lysozymes, on iron-binding proteins, and on the synthesis of toxic cationic polypeptides. Macrophages possess a repertoire of antimicrobial molecules packaged within their granules and lysosomes. These organelles contain a plethora of degradative enzymes and antimicrobial peptides that are released into the phagolysosome, such as proteases, nucleases, phosphatases, esterases, lipases, and highly basic peptides. Moreover, macrophages possess a number of nutrient deprivation mechanisms that are used to starve phagocytosed pathogens of essential micronutrients. Certain microorganisms have evolved countermeasures which enable them to evade being destroyed by phagocytes. Although lysosomal-mediated degradation is an efficient means by which to neutralize an infection and prevent colonization, several pathogens parasitize macrophages, exploiting them as a host cell for growth, maintenance and replication. Parasites like Toxoplasma gondii and mycobacteria are able to prevent fusion of phagosomes with lysosomes, thus escaping the harmful action of lysosomal hydrolases. Others avoid lysosomes by leaving the phagocytic vacuole, to reach the cytosolic matrix where their development is unhindered. In these instances, macrophages may be triggered to actively destroy phagocytosed microorganisms by producing a number of highly toxic molecules and inducing deprivational mechanism to starve it. Finally, some microbes have enzymes to detoxify oxygen metabolites formed during the respiratory burst.

When insufficient to ward off the threat, alveolar macrophages can release proinflammatory cytokines and chemokines to call forth a highly developed network of defensive phagocytic cells responsible for the adaptive immune response.

The lungs are especially sensitive and prone to damage, thus to avoid collateral damage to type 1 and type II pneumocytes, alveolar macrophages are kept in a quiescent state, producing little inflammatory cytokines and displaying little phagocytic activity, as evidenced by downregulated expression of the phagocytic receptor Macrophage 1 antigen (Mac-1). AMs actively suppress the induction of two of the immunity systems of the body: the adaptive immunity and humoral immunity. The adaptive immunity is suppressed through AM’s effects on interstitial dendritic cells, B-cells and T-cells, as these cells are less selective of what they destroy, and often cause unnecessary damage to normal cells. To prevent uncontrolled inflammation in the lower respiratory tract, alveolar macrophages secrete nitric oxide, prostaglandins, interleukin-4 and -10(IL-4, IL-10), and transforming growth factor-β (TGF-β).

Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies. Autoimmune diseases where disease activity is correlated with B cell activity include scleroderma, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and rheumatoid arthritis.

Malignant transformation of B cells and their precursors can cause a host of cancers, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and plasma cell malignancies such as multiple myeloma, Waldenström's macroglobulinemia, and certain forms of amyloidosis.

There is currently minimal therapeutic intervention available for BENTA disease. Patients are closely monitored for infections and for signs of monoclonal or oligoclonal B cell expansion that could indicate B cell malignancy. Splenectomy is unlikely to reduce B cell burden; peripheral blood B cell counts rose significantly in three patients who underwent the procedure. It remains to be determined whether immunosuppressive drugs, including B cell-depleting drugs such as rituximab, could be effective for treating BENTA disease.