The typical patient with lymphocyte-variant hypereosinophilia presents with an extended history of hypereosinophilia and cutaneous allergy-like symptoms. Skin symptoms, which occur in >75% of patients, include erythroderma, pruritis, eczema, Poikiloderma, urticarial, and episodic angioedema. The symptom of episodic angioedema in lymphocyte-variant hypereosinophilia resembles that occurring in Gleich's syndrome, a rare disease that is accompanied by secondary hypereosinophilia plus a sub-population of CD3(-), CD4(+) T cells and therefore proposed, at least in many patients, a subtype of lymphocyte-variant hypereosiophilia. Biopsies of these erythroderma and eczema skin lesions find prominent accumulations of eosinophils. Other presentations include; a) lymphadenopathy occurring in ~60% of patients; b) eosinophil infiltrations in lung similar to, and often diagnosed as, eosinophilic pneumonia, occurring in ~20% of patients; c) episodic angioedema-related gastrointestinal symptoms that are sometimes similar to symptoms of the irritable bowel syndrome occurring in ~20% of patients; d) rheumatologic manifestations of inflammatory arthralgias in ~20% of patients; and e) splenomegaly occurring in ~10% of patients. Cardiovascular complications such as various types of heart damage (see above History section) and vascular injuries due to eosinophil infiltration and eosinophil-induced thrombosis are often critical components of persistent hypereosinohilia syndromes; These complications are not a prominent component of lymphocyte-variant hypereosionophilia, occurring in <10% of patients.

The regulatory T cells (Tregs ), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.

Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer and can facilitate organ transplantation. Their implications for cancer are complicated. Tregs tend to be upregulated in individuals with cancer, and they seem to be recruited to the site of many tumors. Studies in both humans and animal models have implicated that high numbers of Tregs in the tumor microenvironment is indicative of a poor prognosis, and Tregs are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells. Recent immunotherapy research is studying how regulation of T cells could possibly be utilized in the treatment of cancer.

Lymphocyte-variant hypereosinophila, also termed lymphocyte variant eosinophilia, is a rare disorder in which eosinophilia or hypereosinophilia (i.e. a large or extremely large increase in the number of eosinophils in the blood circulation) is caused by aberrant population of lymphocytes. These aberrant lymphocytes function abnormally by stimulating the proliferation and maturation of bone marrow eosinophil-precursor cells termed colony forming unit-Eosinophils or CFU-Eos.

The overly stimulated CFU-Eos cells mature to apparently normal eosinophils, enter the circulation, and may accumulate in, and severely damage, various tissues. The disorder is usually indolent or slowly progressive but may proceed to a leukemic phase and at this phases is sometimes classified as acute eosinophilic leukemia. Hence, lymphocyte-variant hypereosinophilia can be regarded as a precancerous disease.

The order merits therapeutic intervention to avoid or reduce eosinophil-induced tissue injury and to treat its leukemic phase. The latter phase of the disease is aggressive and typically responds relatively poorly to anti-leukemia chemotherapeutic drug regimens.

Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self and foreign lipids and glycolipids. They constitute only approximately 0.1% of all blood T cells. Natural killer T cells should not be confused with natural killer cells.

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.

A lymphocyte is one of the subtypes of white blood cell in a vertebrate's immune system. Lymphocytes include natural killer cells (Phagocytes) (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adaptive immunity), and B cells (for humoral, antibody-driven adaptive immunity). They are the main type of cell found in lymph, which prompted the name "lymphocyte".

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.

Cytokine-induced killer cells or CIK cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL-) 1 and recombinant human interleukin (IL)-2.

Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. However, CIK cells have the ability to recognize infected or even malignant cells in the absence of antibodies and MHC, allowing for a fast and unbiased immune reaction. This is of particular importance as harmful cells that are missing MHC markers cannot be tracked and attacked by other immune cells, such as T-lymphocytes. As a special feature, terminally differentiated CD3+CD56+ CIK cells possess the capacity for both MHC-restricted and MHC-unrestricted anti-tumor cytotoxicity.

These properties, inter alia, rendered CIK cells attractive as a potential therapy for cancer and viral infections.

The primary symptoms of a cytokine storm are high fever, swelling, redness, extreme fatigue, and nausea. In some cases the immune reaction will be fatal.

Certain malignancies cause a secondary eosinophilia or, less commonly, hypereosinophilia. These increases in blood eosinophils appear due to the release of stimulatory cytokines or invasion of the bone marrow and thereby irritation of resident eosinophils or their precursors. Malignancies associated with these effects include gastric, colorectal, lung, bladder, and thyroid cancers, as well as squamous cell cancers of the cervix, vagina, penis, skin, and nasopharyrnx. Some hematological malignancies are likewise associated with secondary rises in blood eosinophil counts; these include Hodgkin disease, certain T-cell lymphomas, acute myeloid leukemia , the myelodysplastic syndromes, many cases of systemic mastocytosis, chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic myelomonocytic leukemia, and certain cases of T-lymphoblastic leukemia/lymphoma-associated or myelodysplastic–myeloproliferative syndrome-associated eosinophilias.

IgG4-related disease or Immunoglobulin G4-related disease is a condition dacryoadenitis, sialadenitis, lymphadentitis, and pancreatitis (i.e. inflammation of the lacrimal glands, salivary glands, lymph nodes, and pancreas, respectively) plus retroperitoneal fibrosis. Less commonly, almost any other organ or tissue except joints and brain may be beleaguered by the inflammatory disorder. About 1/3 of cases exhibit eosinophilia or, rarely, hypereosinophilia. This increase in blood eosinophil count is often associated with abnormal T-lymphocyte clones (e.g increased numbers of CD4 negative, CD7 positive T cells, CD3 negative, CD4 positive T cells, or CD3 positive, CD4 negative, CD8 negative T cells) and is thought to be secondary to these immunological disturbances. The disorder often exhibits are recurrent-relapsing course and is highly responsive to corticosteroids or rituximab as first-line therapy and interferon gamma as second-line therapy.

In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system, e.g., the bone marrow and the thymus) itself, and the lungs in the form of immune-mediated pneumonitis. Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin. Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands.

Acute GvHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients. Skin GvHD results in a diffuse red maculopapular rash, sometimes in a lacy pattern.

Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse.

Acute GvHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GvHD usually have a poor prognosis. If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection.

In the oral cavity, chronic graft-versus-host-disease manifests as lichen planus with a higher risk of malignant transformation to oral squamous cell carcinoma in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients.

Basophils are a type of white blood cells. Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can perform phagocytosis (cell eating), produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting. It used to be thought that basophils that have migrated from blood into their resident tissues (connective tissue) are known as mast cells, but this is no longer thought to be the case.

Basophils were discovered in 1879 by German physician Paul Ehrlich, who one year earlier had found a cell type present in tissues that he termed "mastzellen" (now mast cells). Ehrlich received the 1908 Nobel Prize in Physiology or Medicine for his discoveries.

The name comes from the fact that these leukocytes are basophilic, i.e., they are susceptible to staining by basic dyes, as shown in the picture.

A cytokine storm, also known as cytokine cascade and hypercytokinemia, is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and white blood cells, with highly elevated levels of various cytokines. The term arose in the field of pathophysiology in discussions around immune disorders in 1993, was extended to discussions of infectious disease and sepsis, and has been used to describe severe manifestations of cytokine release syndrome, an adverse effect of some drugs.

Monocytosis is the state of excess monocytes in the peripheral blood. It may be indicative of various disease states.

Examples of processes that can increase a monocyte count include:

- chronic inflammation

- stress response

- Cushing's syndrome (hyperadrenocorticism)

- immune-mediated disease

- granulomatous disease

- atherosclerosis

- necrosis

- red blood cell regeneration

- viral fever

- sarcoidosis

A high count of CD14+CD16++ monocytes is found in severe infection (sepsis)

In the field of atherosclerosis high numbers of the CD14++CD16+ intermediate monocytes were shown to be predictive of cardiovascular events in at risk populations.

The term "NK T cells" was first used in mice to define a subset of T cells that expressed the natural killer (NK) cell-associated marker NK1.1 (CD161). It is now generally accepted that the term "NKT cells" refers to CD1d-restricted T cells, present in mice and humans, some of which coexpress a heavily biased, semi-invariant T-cell receptor and NK cell markers.

The three major types of lymphocyte are T cells, B cells and natural killer (NK) cells. Lymphocytes can be identified by their large nucleus.

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.

In the clinical setting, graft-versus-host-disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction.

- The "acute" or "fulminant" form of the disease (aGvHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality.

- The "chronic" form of graft-versus-host-disease (cGvHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.

Currently, there are no reliable molecular markers reflecting the onset or clinical course of aGVHD. However, it has been shown that genes responsible for cytokine signaling, inflammatory response, and regulation of cell cycle are differentially expressed in patients with fatal GvHD versus "indolent" GvHD.

Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during hematopoiesis in the bone marrow before migrating into blood, after which they are terminally differentiated and do not multiply.

These cells are eosinophilic or "acid-loving" due to their large acidophilic cytoplasmic granules, which show their affinity for acids by their affinity to coal tar dyes: Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, a red dye, using the Romanowsky method. The staining is concentrated in small granules within the cellular cytoplasm, which contain many chemical mediators, such as eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases (DNase), lipase, plasminogen, and major basic protein. These mediators are released by a process called degranulation following activation of the eosinophil, and are toxic to both parasite and host tissues.

In normal individuals, eosinophils make up about 1–3% of white blood cells, and are about 12–17 micrometres in size with bilobed nuclei. While they are released into the bloodstream as neutrophils are, eosinophils reside in tissue They are found in the medulla and the junction between the cortex and medulla of the thymus, and, in the lower gastrointestinal tract, ovary, uterus, spleen, and lymph nodes, but not in the lung, skin, esophagus, or some other internal organs under normal conditions. The presence of eosinophils in these latter organs is associated with disease. For instance, patients with eosinophilic asthma have high levels of eosinophils that lead to inflammation and tissue damage, making it more difficult for patients to breathe. Eosinophils persist in the circulation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence of stimulation. Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, having the capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivo culture experiments.

Langerhans cells are dendritic cells (antigen-presenting immune cells) of the skin and mucosa, and contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the papillary dermis, particularly around blood vessels, as well as in the mucosa of the mouth, foreskin, and vagina. They can be found in other tissues, such as lymph nodes, particularly in association with the condition Langerhans cell histiocytosis (LCH).

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.

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.

Cytokine release syndrome is an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called "cytokine storms", a term borrowed from discussions of the pathophysiology of immune disorders and infectious disease.

CRS has been known since the approval of the first monoclonal antibody drug, Muromonab-CD3, which causes CRS, but people working in the field of drug development at biotech and pharmaceutical companies, regulatory agencies, and academia began to more intensely discuss methods to classify it and how to mitigate its risk following the disastrous 2006 Phase I clinical trial of TGN 1412, in which the six subjects experienced severe CRS.