Inherited Disorders
Although there are few inherited causes of lymphocytosis, such is not the case for lymphocytopenia, in which the genetic bases of a number of inherited immunodeficiency disorders have been identified. Chief among these disorders is severe combined immunodeficiency (SCID), which is characterized by the absence of functional T lymphocytes. T lymphocytes, B lymphocytes, and NK cells share progenitors, signaling pathways in development and function, and metabolic pathways; thus B lymphocytes, NK cells, or both are often severely affected in SCID. Moreover, in the absence of functional CD4+ T-helper lymphocytes, B lymphocytes cannot function properly, and hypogammaglobulinemia or agammaglobulinemia is observed. In most cases of SCID, the absence of T lymphocytes leads to an extremely low absolute lymphocyte count. In general, SCID is characterized by complete loss of function of the affected gene, whereas hypomorphic mutations of the same genes lead to quite different phenotypes, including Omenn syndrome and “leaky SCID” in which there is some development of T cells but with limited function and repertoire. Defects in more than 30 genes are known to lead to SCID. Inheritance is primarily X-linked or autosomal recessive, but in a few cases, such as the DiGeorge anomaly and some cases of Hoyeraal-Hreidarsson syndrome (defects in telomerase), inheritance is autosomal dominant. In the past, it was useful to characterize SCID syndromes as T−B+NK+, T−B−NK+, T−B+NK−, or T−B−NK− based on the presence or absence of defects affecting B and/or NK cells. SCID can be classified based on the cellular function which is lacking, including deficiency in cytokine-mediated signaling, defects in V(D) J recombination, absent signaling through the T-cell receptor, defects in antigen presentation, and defects in basic cellular processes; the genetic defects for a number of syndromes are now known. Defects in the interleukin (IL)-7 receptor alpha chain (IL7RA), actin-regulating protein coronin 1 A (CORO1A), CD3 chain components (CD3D, CD3E, CD247), and CD45 (PTPRC) lead to T−B+NK+ SCID. T−B+NK− SCID defects include deficiencies in cytokine-mediated signaling (IL2RG, JAK3). Defects in V(D)J recombination (RAG1, RAG2) or in nonhomologous end joining for repair of double-strand DNA breaks (DCLRE1C, PRKDC, LIG4, and NHEJ1 mutations) lead to T−B−NK+ SCID. Defects that lead to increased lymphocyte apoptosis (AK2, ADA gene mutations) lead to T−B−NK− SCID and are often associated with anomalies outside of the immune system. Defects in thymic embryogenesis and calcium flux, as well as a collection of other abnormalities, including defects in telomerase activity, can also lead to SCID and are usually associated with abnormalities of other organ systems.
In addition to SCID, other inherited disorders can also perturb T- and B-cell numbers. Patients with classic Wiskott-Aldrich syndrome, caused by mutations in WAS (which encodes a cytoplasmic protein responsible for transducing cell surface signals to the actin cytoskeleton), can present with low T-cell counts early in life and become profoundly lymphopenic over time. Abnormalities in immunoglobulins are also noted in this syndrome, with low levels of IgM and high levels of IgA and IgE. X-linked thrombocytopenia is also due to mutations in WAS, although clinical presentation is milder probably due to preservation of partial WAS protein expression. Immunodeficiency affects more than half of all patients with ataxia telangiectasia. Patients with ataxia telangiectasia have homozygous or compound heterozygous mutations in the ataxia-telangiectasia–mutated (ATM) gene, which encodes a protein kinase with functions in the cellular response to DNA damage. Lymphopenia, especially of naive CD4 cells, is observed in approximately half of patients with ataxia telangiectasia, with mutations leading to absent expression of ATM kinase activity. Heterozygous germline mutations in GATA2 lead to a spectrum of clinical syndromes characterized by dendritic cell, monocyte, B cell, and NK lymphoid deficiency (DCML deficiency) with elevated Fms-related tyrosine kinase 3 ligand (Flt3L). Mononuclear cytopenia appears to evolve in diverse clinical groups of GATA2 mutation, including monoMAC syndrome (monocytopenia, B-cell and NK-cell lymphopenia, mycobacterial, fungal, and viral infections and alveolar proteinosis), Emberger syndrome (lymphedema, deaf ness, and myelodysplastic syndrome [MDS]), and familial (MDS)/ acute myeloid leukemia (AML). GATA2 mutation appears to cause loss of progenitor cells, clonal hematopoiesis, and elevation of Flt3L, but the molecular mechanisms of marrow failure and transformation to MDS or AML are as yet unclear.
Infections
A variety of viral and nonviral infections can lead to lymphopenia. HIV is the most common virus associated with lymphopenia. The target of HIV is the CD4 receptor, and the virus selectively tar gets and infects activated expanding CD4 T cells. Large studies in HIV-infected patients have shown that peripheral blood CD4 T-cell counts decrease most rapidly in the year after seroconversion (from approximately 1000/μL before seroconversion to 670/μL at 1 year after infection) and then decline more slowly by approximately 50/ μL per year. In a subset of untreated patients, viremia is absent or well controlled, and lymphocytopenia develops very slowly if at all; HLA class I alleles, in particular HLA-B, are overrepresented in this group as are rare variants in genes involved in innate immune sensing, CD4-dependent infectivity, HIV trafficking, and HIV transcription. Lymphopenia is an early and reliable laboratory observation in adult influenza infection and is also detected in infections caused by swine influenza (H1N1) and the highly pathogenic avian influenza (H5N1). Lymphopenia has been reported in patients with severe acute respiratory syndrome (SARS) caused by the SARS-coronavirus. Mild illness due to SARS-CoV-2 infection produces lymphopenia in approximately a third of patients, but early reports from Wuhan, China demonstrate that lymphopenia occurred in more than 80% of critically ill patients. In children, respiratory syncytial virus (RSV) infection is associated with a reduction in lymphocyte count, which is most extreme in the sickest patients; similar effects on lymphocyte counts are seen in measles infections (also a paramyxovirus). In West Nile virus encephalitis, lymphopenia is profound and prolonged, and the initial degree of lymphopenia is predictive of outcome. A variety of other viruses can also cause lymphopenia, including herpes viruses (herpes simplex, HHV-6, HHV-8), parvovirus B19, and Dengue virus. In many viral infections, the degree of lymphopenia is correlated with the severity of the disease.
A variety of nonviral infections causes lymphopenia. Infections with Ehrlichia (a tick-borne obligate intracellular gram-negative bacteria), Salmonella typhi, and Leptospira have all been reported to cause lymphocytopenia during the acute illness. CD4+ T-cell depletion has been described in a subset of HIV-negative patients with tuberculosis and low albumin levels, low body weight, and more extensive disease. Recovery of CD4 count after treatment of tuberculosis suggests that the lymphopenia is caused by the tuberculosis infection. Lymphocytopenia is often observed in sepsis and is thought to occur as a result of cytokine mediated apoptosis of B cells, CD4 and CD8 T cells, and follicular dendritic cells. In autopsy series, most deaths from sepsis occur during the prolonged hypoimmune state, and the more prolonged the sepsis, the more profound the loss of splenic lymphocytes. In one large retrospective study, severe persistent lymphopenia (defined as an absolute lymphocyte count of less than 600 cells/μL) on the fourth day following a diagnosis of sepsis was predictive of development of secondary infections, as well as short- and long-term survival.
Collagen Vascular Disorders
Autoimmune diseases frequently exhibit decreases in circulating lymphocytes. In systemic lupus erythematosus (SLE), lymphopenia (usually decreases in T cells but occasionally in B cells as well) is not only one of the diagnostic criteria but also a parameter used to assess disease activity. Lymphopenia was observed in more than 60% of patients at diagnosis, with the cumulative incidence over the course of the disease reaching more than 90%. Lymphopenia in SLE seems to be more frequent in patients of African descent, and in one study more than half of patients with lymphopenia demonstrated antilymphocyte anti bodies. Antigalectin 8 antibodies have been described in patients with SLE, rheumatoid arthritis, and sepsis. In SLE, these autoantibodies are associated with lymphopenia. Apoptosis may also play a role in lymphopenia in SLE, possibly by upregulation of fas antigen on naive peripheral T cells. CD4 T cells may also be decreased in rheumatoid arthritis, and increasing evidence suggests that deficiencies in DNA repair enzymes such as ATM render rheumatoid arthritis T cells sensitive to apoptosis. Apoptotic loss of naive T cells results in lymphopenia-induced proliferation to preserve T-cell homeostasis; this proliferation is now thought to lead to both premature immune aging and an autoimmune-biased T-cell repertoire. In Sjögren syndrome, a minority of patients has been noted to have deficient CD4 counts, and this has been correlated with the presence of anti-CD4 antibodies. Similarly, low lymphocyte counts have been observed in patients with primary vasculitides, type 1 diabetes, and Crohn disease.
Malignancies
Lymphopenia is found in a variety of systemic illnesses; chief among them are cancers. In hematologic malignancies, including Hodgkin lymphoma, diffuse large B-cell lymphoma, and peripheral T-cell lymphoma, patients with lymphopenia have a worse prognosis. Lymphopenia has also been observed in solid tumors, including breast and colon cancer, and soft tissue sarcomas, in which its presence before treatment predicts decreased overall survival. Which specific lymphocyte subsets are involved and the cause(s) of lymphopenia in these tumor types have not been described.
Systemic Disorders
End-stage renal disease (ESRD) has also been associated with lymphopenia, an observation not thought to be exclusively attributable to an effect of dialysis alone. Naive and central memory CD4 and CD8 T cells are significantly reduced in the blood of ESRD patients, apparently because of increased susceptibility of these cells to apoptosis. Lymphopenia occurs in more than 50% of sarcoidosis patients and is associated with chronic disease. Sarcoidosis patients with severe organ system involvement, including neurologic, cardiac, ocular, and advanced pulmonary disease, have lower lymphocyte counts than patients with less severe manifestations (see E-Slide VM03953). Older studies suggest that burn victims have profound decreases in T-cell counts, which may contribute to the infection risk in these patients. Interestingly, lymphopenia is a characteristic of both protein-energy malnutrition and zinc deficiency. Both of these deficiencies perturb the hypothalamic-pituitary-adrenocorticoid axis and increase glucocorticoid levels, which results in increased apoptosis of B and T cells. Intestinal lymphangiectasia, which may be either con genital or secondary to processes that obstruct lymphatic drainage of the gastrointestinal tract, can cause lymphopenia as a result of loss of lymph fluid into the gut along with lymphocytes.
A rare cause of lymphopenia is idiopathic CD4+ lymphocytopenia (ICL), which is defined as a CD4 count less than 300/μL or less than 20% of the T-cell count on two occasions that is not caused by HIV or HTLV infection, drug therapy, or a known immunodeficiency. Patients usually come to clinical notice when they present with opportunistic infections. CD4 T-cell counts typically remain low, but counts do not continue to drop or do not decrease rapidly after diagnosis. In one large series, only approximately 20% of patients recovered from lymphopenia within 3 years of diagnosis. Opportunistic infections plague these patients, and autoimmune diseases occur both before and after the diagnosis of ICL. In ICL, unlike HIV infection, increased activation and turnover are observed in CD4 but not CD8 T lymphocytes.
Drug Effects
A number of drugs are known to cause lymphopenia. Glucocorticoids inhibit production of a number of cytokines and rapidly deplete circulating T cells by enhancing emigration from the circulation, inducing apoptosis, interfering with growth signaling, and inhibiting release from lymphoid tissues. B cells are less affected acutely by glucocorticoid administration, but prolonged administration may result in decreased IgG levels. In clinical trials for multiple sclerosis, delayed-release dimethyl fumarate resulted in a decrease in mean lymphocyte count of approximately 30% in the first year, but approximately 2% of patients had lymphocyte counts less than 500 cells/μL, which persisted for 6 months or longer. Antimetabolite chemotherapeutic agents such as methotrexate, azathioprine, and 6-mercaptopurine lower lymphocyte as well as neutrophil counts, and alkylating agents such as cyclophosphamide have more profound effects on lymphocytes. Purine nucleoside analogs, including cladribine, fludarabine, pentostatin, nelarabine, clofarabine, and others, inhibit DNA synthesis and repair and cause accumulation of DNA strand breaks. All of these agents are associated with profound lymphopenia, which may persist for several years after completion of treatment. In general, T cells are more affected than B cells. Nelarabine in particular is a prodrug of ara-G and is converted to arabinosylguanine triphosphate (ara-GTP), which accumulates at higher levels in T cells.
Monoclonal and polyclonal antibodies directed against lymphocytes are useful in clinical practice and can induce profound and long lasting lymphopenia. Antithymocyte globulin and alemtuzumab produce depletion of both T and B cells, whereas the monoclonal antibodies OKT3, daclizumab, and basiliximab produce a more pronounced decrease in T cells. The drugs rituximab and ofatumumab are monoclonal antibodies directed against distinct epitopes on B cells. These drugs deplete peripheral B cells but do not routinely produce lymphopenia.
Finally, radiation exposure commonly results in lymphopenia, which occurs before depression of other cell counts. In fact, lymphopenia can develop within the first 24 hours of exposure if the dose of radiation is great enough. Irradiation of the bone marrow, spleen, lymph nodes, and the tumor can all produce lymphopenia. The spleen and lymph nodes are lymphocyte reservoirs and sites for clonal expansion of lymphocytes to specific antigens. Lymphocytes circulating through the radiation portal receive a dose of radiation with each fraction which can result in lymphopenia, particularly when one considers that the D50 (dose required for inactivation of 50% of cells) for lymphocytes is only approximately 2 gray. Some patients never recover their lymphocyte count, and this is thought to be due both to the radiation-related destruction of lymphocytes and lack of a surge in compensatory cytokines IL-7 and IL-15 to produce clonal expansion of lymphocytes, maturation, and formation of memory cells.
