Biomarkers of Immunity: Lymphocytes

Optimal Takeaways

Lymphocytes are white blood cells that protect against microbial infection and help regulate inflammation. A decreased lymphocyte level is associated with immune compromise, more severe infection, and inflammation. Elevated levels are associated with chronic infection, leukemia, lymphoma, metabolic syndrome, type 2 diabetes, and steroid use.

Lymphocytes, Absolute             

Standard Range: 0.85 - 3.9 k/cumm

The ODX Range: 1.44 – 2.54 k/cumm

Lymphocytes %                    

Standard Range: 14.00 – 46.00%

The ODX Range: 30.00 – 35.00%  

Low lymphocyte counts are associated with sepsis, immunodeficiency diseases, late-stage HIV infection, leukemia, systemic lupus erythematosus, strenuous exercise, nicotine use, and drug therapy, including adrenocorticosteroids, antineoplastic agents, and immunosuppressive therapy (Pagana 2022).

Low lymphocytes are also associated with all-cause mortality, cardiovascular disease, inflammation (Zidar 2019), malnutrition (Leandro-Merhi 2019), protein-energy malnutrition, poor clinical outcomes, increased severity of COVID-19 (Zhang 2022), COVID-19 mortality and intubation (Illg 2021), decreased overall survival in hepatic (Yu 2021), colorectal, breast, and renal carcinoma (Zhao 2020).

High lymphocyte counts may be observed with chronic bacterial infection, viral infection including mumps and rubella, lymphocytic leukemia, lymphoma, multiple myeloma, mononucleosis, infectious hepatitis, radiation exposure, chronic inflammatory conditions, and steroid use (Pagana 2022). Elevated lymphocytes are also associated with metabolic syndrome (Babio 2013) and type 2 diabetes (Gkrania 2010).

Overview

Lymphocytes are a type of nongranulocyte mononuclear white blood cell. Along with neutrophils, they account for the majority of WBCs in circulation. The primary job of lymphocytes is to fight chronic bacterial or acute viral infections. Lymphocytes facilitate adaptive immunity and include B cells and T cells. Antibody-producing B-cells participate in humoral immunity, while T-cells enable cellular-type immune reactions and include CD4 T-helper cells and cytotoxic CD8 T-suppressor cells. The ratio of CD4 to CD8 cells can provide valuable prognostic information (Pagana 2022). The B cells mature in the bone marrow, while T cells mature in the thymus gland. Both types of cells leave these primary lymphoid sites and migrate to secondary lymphoid sites such as the lymph nodes, tonsils, spleen, liver, skin, and mucosa, where they can identify and respond to various antigens via the actions of antibodies and/or cytokines (Justiz 2022). The human microbiota and its byproducts, including short-chain fatty acids, influence B and T cell development and may be an underlying factor in immune dysfunction in some individuals (Schirmer 2018).

The T-helper (Th) subset of lymphocytes includes many cells with different functions. For example, Th1 cells produce interferon compounds that can activate macrophages to fight off intracellular bacteria or to activate cytotoxic T lymphocytes that fight off viruses. Th2 cells produce cytokines that activate eosinophils, mast cells, and goblet cells to fight off helminth (worm) infection. The T17 cells facilitate an inflammatory response to help neutrophils resist extracellular bacterial infection. T-helper cells also contribute to the pathophysiology of allergic, inflammatory, and autoimmune diseases (Koyasu 2012).

Natural killer (NK) cells are another class of lymphocytes that participates in innate immunity and helps control pathogenic infection and cancer cell proliferation via cytokine production and cytotoxic activities. Natural killer cells also help control inflammation and may reduce the risk of inflammatory disorders by controlling infections and eliminating activated macrophages and other activated cells (Vivier 2008). The NK cells have innate and adaptive immune functions, including antigen-specific memory (Vivier 2011). Lymphocytes comprise 20-40% of the total white blood cell count (Tigner 2021). Lymphocytes may be expressed as a percentage of total white blood cells (relative lymphocytes) or as absolute lymphocytes. Some research may calculate total lymphocytes, which account for absolute lymphocytes plus all large lymphocytes, such as reactive lymphocytes or lymphoblasts (Sreenivasan 2011). However, labs are likely to report absolute lymphocytes versus total lymphocytes.

A decreased lymphocyte count is associated with immune compromise and severe infection (Pagana 2022). However, it is also a marker for malnutrition, a risk factor for increased morbidity and mortality, especially among hospitalized patients. In one cross-sectional study, nutrition risk increased by 4.6% for every 0.1 k/cumm decrease in lymphocyte count (Leandro-Merhi 2019).

A low lymphocyte count is also associated with COVID-19. The SARS-CoV-2 virus that causes COVID-19 directly attacks lymphocytes, complicating recovery from this pandemic. A prospective study of 101 COVID-19 patients found that a low lymphocyte count of 0.75 k/cumm versus 1.64 k/cumm was associated with malnutrition, anorexia, organ failure, and comorbidities, including diabetes and cancer. Researchers note that a lymphocyte count below 1.5 k/cumm is generally associated with malnutrition, while a level below 0.9 k/cumm is associated with severe malnutrition (Zhang 2022).

A higher lymphocyte count was associated with an increased risk of developing metabolic syndrome in a cross-sectional and prospective evaluation of 4,377 individuals without metabolic syndrome at baseline, followed up over an average of 3.9 years. A median absolute lymphocyte count of 2.55 k/cumm was associated with a significantly increased risk of metabolic syndrome compared to the lowest quartile of 1.54 k/cumm. Metabolic syndrome was also associated with the highest quartiles of total WBCs and neutrophils (Babio 2013).

Diabetes is also associated with absolute lymphocytes above optimal, according to a systematic review and meta-analysis comprising 15,550 men and women 40-79 years old. The highest risk of type 2 diabetes was associated with a mean absolute lymphocyte count of 2.78 k/cumm or above, while the lowest risk was associated with a mean of 1.44 k/cumm (Gkrania-Klotsas 2010). In older community-dwelling women aged 65-101, an absolute lymphocyte count below 1.54 k/cumm was associated with increased all-cause mortality (Leng 2005).

The absolute lymphocyte count indicates the total number of cells in circulation, while %lymphocytes indicate the percentage of white blood cells made up of lymphocytes.

References

Babio, Nancy et al. “White blood cell counts as risk markers of developing metabolic syndrome and its components in the PREDIMED study.” PloS one vol. 8,3 (2013): e58354. doi:10.1371/journal.pone.0058354

Gkrania-Klotsas, Effrossyni et al. “Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies.” PloS one vol. 5,10 e13405. 18 Oct. 2010, doi:10.1371/journal.pone.0013405

Illg, Zachary et al. “Analysis of absolute lymphocyte count in patients with COVID-19.” The American journal of emergency medicine vol. 46 (2021): 16-19. doi:10.1016/j.ajem.2021.02.054

Justiz Vaillant, Angel A., et al. “Physiology, Immune Response.” StatPearls, StatPearls Publishing, 26 September 2022.

Koyasu, Shigeo, and Kazuyo Moro. “Role of innate lymphocytes in infection and inflammation.” Frontiers in immunology vol. 3 101. 7 May. 2012, doi:10.3389/fimmu.2012.00101

Leandro-Merhi, Vânia Aparecida et al. “NUTRITIONAL INDICATORS OF MALNUTRITION IN HOSPITALIZED PATIENTS.” Arquivos de gastroenterologia vol. 56,4 (2019): 447-450. doi:10.1590/S0004-2803.201900000-74

Leng, Sean X et al. “Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women.” Experimental gerontology vol. 40,12 (2005): 982-7. doi:10.1016/j.exger.2005.08.006

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Pahwa, Roma, et al. “Chronic Inflammation.” StatPearls, StatPearls Publishing, 8 August 2022.

Schirmer, M., Kumar, V., Netea, M.G., Xavier, R.J. (2018). The causes and consequences of variation in human cytokine production in health. Current Opinion in Immunology, 54:50-58. doi:10.1016/j.coi.2018.05.012.

Sreenivasan, Srirangaraj, and Venkatesha Dasegowda. “Comparing absolute lymphocyte count to total lymphocyte count, as a CD4 T cell surrogate, to initiate antiretroviral therapy.” Journal of global infectious diseases vol. 3,3 (2011): 265-8. doi:10.4103/0974-777X.83533

Tigner, Alyssa, et al. “Histology, White Blood Cell.” StatPearls, StatPearls Publishing, 19 November 2021.

Vivier, Eric et al. “Functions of natural killer cells.” Nature immunology vol. 9,5 (2008): 503-10. doi:10.1038/ni1582

Vivier, Eric et al. “Innate or adaptive immunity? The example of natural killer cells.” Science (New York, N.Y.) vol. 331,6013 (2011): 44-9. doi:10.1126/science.1198687

Yu, Jeong Il et al. “Clinical importance of the absolute count of neutrophils, lymphocytes, monocytes, and platelets in newly diagnosed hepatocellular carcinoma.” Scientific reports vol. 11,1 2614. 28 Jan. 2021, doi:10.1038/s41598-021-82177-5

Zhang, Kai et al. “Malnutrition Contributes to Low Lymphocyte Count in Early-Stage Coronavirus Disease-2019.” Frontiers in nutrition vol. 8 739216. 6 Jan. 2022, doi:10.3389/fnut.2021.739216

Zhao, Jiawen et al. “Prognostic role of pretreatment blood lymphocyte count in patients with solid tumors: a systematic review and meta-analysis.” Cancer cell international vol. 20 15. 10 Jan. 2020, doi:10.1186/s12935-020-1094-5

Zidar, David A et al. “Association of Lymphopenia With Risk of Mortality Among Adults in the US General Population.” JAMA network open vol. 2,12 e1916526. 2 Dec. 2019, doi:10.1001/jamanetworkopen.2019.16526