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.

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".

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.

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

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 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

Eosinophils compose about 2-4% of the WBC total. This count fluctuates throughout the day, seasonally, and during menstruation. It rises in response to allergies, parasitic infections, collagen diseases, and disease of the spleen and central nervous system. They are rare in the blood, but numerous in the mucous membranes of the respiratory, digestive, and lower urinary tracts.

They primarily deal with parasitic infections. Eosinophils are also the predominant inflammatory cells in allergic reactions. The most important causes of eosinophilia include allergies such as asthma, hay fever, and hives; and also parasitic infections. They secrete chemicals that destroy these large parasites, such as hook worms and tapeworms, that are too big for any one WBC to phagocytize. In general, their nucleus is bi-lobed. The lobes are connected by a thin strand. The cytoplasm is full of granules that assume a characteristic pink-orange color with eosin staining.

Neutrophils are the most abundant white blood cell, constituting 60-70% of the circulating leukocytes. They defend against bacterial or fungal infection. They are usually first responders to microbial infection; their activity and death in large numbers form pus. They are commonly referred to as polymorphonuclear (PMN) leukocytes, although, in the technical sense, PMN refers to all granulocytes. They have a multi-lobed nucleus, which consists of three to five lobes connected by slender strands. This gives the neutrophils the appearance of having multiple nuclei, hence the name polymorphonuclear leukocyte. The cytoplasm may look transparent because of fine granules that are pale lilac when stained. Neutrophils are active in phagocytosing bacteria and are present in large amount in the pus of wounds. These cells are not able to renew their lysosomes (used in digesting microbes) and die after having phagocytosed a few pathogens. Neutrophils are the most common cell type seen in the early stages of acute inflammation. The life span of a circulating human neutrophil is about 5.4 days.

The most common cause of temporary lymphocytopenia is a recent infection, such as the common cold.

Lymphocytopenia, but not idiopathic CD4+ lymphocytopenia, is associated with corticosteroid use, infections with HIV and other viral, bacterial, and fungal agents, malnutrition, systemic lupus erythematosus, severe stress, intense or prolonged physical exercise (due to cortisol release), rheumatoid arthritis, sarcoidosis, and iatrogenic (caused by other medical treatments) conditions.

Lymphocytopenia is a frequent, temporary result from many types of chemotherapy, such as with cytotoxic agents or immunosuppressive drugs. Some malignancies that have spread to involve the bone marrow, such as leukemia or advanced Hodgkin's disease, also cause lymphocytopenia.

Another cause is infection with Influenza A virus subtype H1N1 (and other subtypes of the Influenza A virus) and is then often associated with Monocytosis; H1N1 was responsible for the Spanish flu, the 2009 flu pandemic and in 2016 for the Influenza-epidemic in Brazil.

Large doses of radiation, such as those involved with nuclear accidents or medical whole body radiation, may cause lymphocytopenia.

Treatment for X-linked SCID can be divided into two main groups, the prophylactic treatment (i.e. preventative) and curative treatment. The former attempts to manage the opportunistic infections common to SCID patients and the latter aims at reconstituting healthy T-lymphocyte function.

From the late 60s to early 70s, physicians began using "bubbles", which were plastic enclosures used to house newborns suspected to have SCIDS, immediately after birth. The bubble, a form of isolation, was a sterile environment which meant the infant would avoid infections caused by common and lethal pathogens. On the other hand, prophylactic treatments used today for X-linked SCID are similar to those used to treat other primary immunodeficiencies. There are three types of prophylactic treatments, namely, the use of medication, sterile environments, and intravenous immunoglobulin therapy (IVIG). First, antibiotics or antivirals are administered to control opportunistic infections, such as fluconazole for candidiasis, and acyclovir to prevent herpes virus infection. In addition, the patient can also undergo intravenous immunoglobulin (IVIG) supplementation. Here, a catheter is inserted into the vein and a fluid, containing antibodies normally made by B-cells, is injected into the patient's body. Antibodies, Y-shaped proteins created by plasma cells, recognize and neutralize any pathogens in the body. However, the IVIG is expensive, in terms of time and finance. Therefore, the aforementioned treatments only prevent the infections, and are by no means a cure for X-linked SCID.

Bone marrow transplantation (BMT) is a standard curative procedure and results in a full immune reconstitution, if the treatment is successful. Firstly, a bone marrow transplant requires a human leukocyte antigen (HLA) match between the donor and the recipient. The HLA is distinct from person to person, which means the immune system utilizes the HLA to distinguish self from foreign cells. Furthermore, a BMT can be allogenic or autologous, which means the donor and recipient of bone marrow can be two different people or the same person, respectively. The autologous BMT involves a full HLA match, whereas, the allogenic BMT involves a full or half (haploidentical) HLA match. Particularly, in the allogenic BMT the chances of graft-versus-host-disease occurring is high if the match of the donor and recipient is not close enough. In this case, the T-cells in the donor bone marrow attack the patient's body because the body is foreign to this graft. The depletion of T-cells in the donor tissue and a close HLA match will reduce the chances of graft-versus-host disease occurring. Moreover, patients who received an exact HLA match had normal functioning T-cells in fourteen days. However, those who received a haploidentical HLA match, their T-cells started to function after four months. In addition, the reason BMT is a permanent solution is because the bone marrow contains multipotent hematopoietic stem cells which become common lymphoid or common myeloid progenitors. In particular, the common lymphoid progenitor gives rise to the lymphocytes involved in the immune response (B-cell, T-cell, natural killer cell). Therefore, a BMT will result in a full immune reconstitution but there are aspects of BMT that need to be improved (i.e. GvHD).

Gene therapy is another treatment option which is available only for clinical trials. X-linked SCID is a monogenic disorder, the IL2RG gene is mutated, so gene therapy will replace this mutated gene with a normal one. This will result in a normal functioning gamma chain protein of the interleukin receptor. In order to transfer a functional gene into the target cell, viral or non-viral vectors can be employed. Viral vectors, such as the retrovirus, that incorporate the gene into the genome result in long-term effects. This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID. In one particular trial by Cavazzana-Calvo et al., ten children were treated with gene therapy at infancy for X-SCID. Nine of the ten were cured of X-SCID. However, about three years after treatment, two of the children developed T-cell leukemia due to insertion of the IL2RG gene near the LMO2 gene and thereby activating the LMO2 gene (a known oncogene). A third child developed leukemia within two years of that study being published, likely as a direct result of the therapy. This condition is known as insertional mutagenesis, where the random insertion of a gene interferes with the tumor suppressor gene or stimulates an oncogene. There is currently no approved gene therapy on the market, but there are many clinical trials into which X-SCID patients may enroll. Therefore, research in the field of gene therapy today and in the future is needed to avoid the occurrence of leukemia. In particular, research into the use of insulator and suicide genes is warranted as this may prevent cancer from developing. The insulator gene inhibits the activation of adjacent genes. On the other hand, the suicide gene is stimulated when a tumour begins to form, and this will result in the deactivation of the therapeutic gene. Moreover, the use of restriction enzymes such as the zinc-finger nuclease (ZFN) is being studied. The ZFN allows the researcher to choose the site of gene integration. Vector safety is important in the field of gene therapy, hence vectors that self-inactivate the promoter and enhancer (SIN) and adenoviruses that creates no immune response are prominent areas of research for vector biologists.

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.

In terms of treatment for hyper Igm syndrome there is the use of allogeneic hematopoietic cell transplantation. Additionally anti-microbial therapy, use of granulocyte colony-stimulating factor, immunosuppressants, as well as, other treatments may be needed.

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells. In the absence of T cell help, B cells become defective. It is an x-linked recessive trait, stemming from a mutated (abnormal) version of the IL2-RG gene located at xq13.1 on the X-chromosome, which is shared between receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

Lymphocytopenia caused by Feline Leukemia Virus and Feline immunodeficiency virus retroviral infections is treated with Lymphocyte T-Cell Immune Modulator.

Gene therapy is a relatively new concept in the field of SCID. This therapy is currently undergoing clinical trial and has cured a small number of children suffering from X-linked SCID and recessive allele SCID. Gene therapy aims to correct the underlying genetic abnormality in SCID. In the case of RD, the genetic abnormality would be AK2 malfunction. Stem cells are taken from an affected child's blood or bone marrow. Then in laboratory conditions the stem cells are manipulated and corrected with gene technology. They are then injected back into the patient. Similarly, in bone transplant, stem cells are able to find their way back through tracking mechanisms.

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.

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) can be used as a temporary cure. GM-CSF stimulates production of white blood cells. This cure is commonly used in patients who are awaiting bone marrow transplantation. Response to this cure can vary. Those with a more severe combined immunodeficiency may have no response to this therapy.

Current research is aimed at studying large cohorts of people with CVID in an attempt to better understand age of onset, as well as mechanism, genetic factors, and progression of the disease.

Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012, and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following:

- Causes of complications. Little is known about why such diverse complications arise during treatment

- Underlying genetic factors. Though many polymorphisms and mutations have been identified, their respective roles in CVID development are poorly understood, and not represented in all people with CVID.

- Finding new ways to study CVID. Given that CVID arises from more than one gene, gene knock-out methods are unlikely to be helpful. It is necessary to seek out disease related polymorphisms by screening large populations of people with CVID, but this is challenging given the rarity of the disease.

Treatment for "B cell deficiency"(humoral immune deficiency) depends on the cause, however generally the following applies:

- Treatment of infection(antibiotics)

- Surveillance for malignancies

- Immunoglobulin replacement therapy

Hyper IgM syndromes is a group of primary immune deficiency disorders characterized by defective CD40 signaling; "via" B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch recombination deficiencies are characterized by elevated serum Immunoglobulin M (IgM) levels and a considerable deficiency in Immunoglobulins G (IgG), A (IgA) and E (IgE). As a consequence, people with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections.

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.

Treatment consists of immunoglobulin replacement therapy, which replenishes Ig subtypes that the person lack. This treatment is given at frequent intervals for life, and is thought to help reduce bacterial infections and boost immune function. Before therapy begins, plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG samples. Infusions can be administered in three different forms: intravenously (IVIg):, subcutaneously (SCIg), and intramuscularly (IMIg).

The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands. Because highly concentrated product is used, IVIg infusions take place every 3 to 4 weeks. Subcutaneous infusions slowly release the Ig serum underneath the skin, again through a needle, and takes place every week. Intramuscular infusions are no longer widely used, as they can be painful and are more likely to cause reactions.

People often experience adverse side effects to immunoglobulin infusions, including:

- swelling at the insertion site (common in SCIG)

- chills

- headache

- nausea (common in IVIG)

- fatigue (common in IVIG)

- muscle aches and pain, or joint pain

- fever (common in IVIG and rare in SCIG)

- hives (rare)

- thrombotic events (rare)

- aseptic meningitis (rare, more common in people with SLE)

- anaphylactic shock (very rare)

In addition to Ig replacement therapy, treatment may also involve immune suppressants, to control autoimmune symptoms of the disease, and high dose steroids like corticosteroids. In some cases, antibiotics are used to fight chronic lung disease resulting from CVID. The outlook for people varies greatly depending on their level of lung and other organ damage prior to diagnosis and treatment.

The mainstay of treatment consists of thymectomy and immunoglobulin replacement with IVIG (Kelesidis, 2010). Immunodeficiency does not resolve after thymectomy (Arnold, 2015). To treat the autoimmune component of the disease, immune-suppression is sometimes used and it is often challenging to determine if a patient’s symptoms are infectious or autoimmune (Arnold, 2015).

Patients should have serological testing for antibodies to toxoplasma and cytomegalovirus. If receiving a transfusion, CMV negative blood should be used in those with negative serological testing. Live vaccines should also be avoided (Kelesidis, 2010). The CDC recommends pneumococcal, meningococcal, and Hib vaccination in those with diminished humoral and cell-mediated immunity (Hamborsky, 2015).

Some have advocated treating prophylactically with TMP-SMX if CD4 counts are lower than 200 cells/mm^3, similar to AIDS patients (Kelesidis, 2010).