Introduction

White blood cells are lymphocytes that play a key role in adaptive immunity. Lymphocytosis occurs when the number of lymphocytes in the human blood is greater than 4 x 10⁹/ L.¹ It is associated with both autoimmune disorders and chronic inflammation.^2,3 Inflammatory responses are commonly triggered by multiple factors like bacterial, viral, parasitic, and fungal infections, being crucial in initiating the stages of inflammation—acute, subacute, and chronic.^1,2,3,4,6

Chronic inflammatory conditions: Activation of immune system

Persistent inflammation may lead to chronic inflammatory diseases (CID) like inflammatory bowel diseases and autoimmune disorders.^{2, 3} In order to understand them, first of all we need to know about the factors responsible for the inflammation and identify the immune cells that are exclusively involved in both chronic inflammatory disorders and autoimmune conditions. 

What happens in inflammation?

The immune system is activated after the invasion of microbes—infection or any other reason—this process is called inflammation. Depending upon the duration of inflammation, this is divided in to two types:^4,6

• Acute: It lasts for a short time, and in it, symptoms appear rapidly
• Chronic inflammation: This persists for a longer period, and acute symptoms lead to chronic inflammatory conditions

Causes of inflammation:

Stimuli that trigger cellular inflammation are damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs).⁵ They act as stimuli for initiating three stages of inflammation, starting from acute to sub-acute and ending at chronic inflammation^{5, 6}

• DAMPs are derived from host cells, for example, lipids and heat shock proteins (HSPs)^5,6
• PAMPs are flagellins and lipopolysaccharides (LPS) from bacterial diseases like Tuberculosis, otitis media and bronchitis and Viral infections like influenza and hepatitis^4,5,6

Which types of immune cells are involved in chronic inflammatory conditions?

Upon encountering DAMPs and PAMPs, the initial immune response is mediated by innate immune cells, such as:

• Basophils
• Neutrophils
• Natural killer cells (NKs) 
• Eosinophils

Some of them are phagocytic cells and behave like  antigen-presenting cells (APCs) to macrophages and lymphocytes. Among monocytic cells, macrophages and dendritic cells (DCs) also play a crucial role in innate immunity, whereas lymphocytes, including B cells and T cells, perform functions in the adaptive immune system

• T cells are differentiated into cytotoxic T cells (CTLs), regulatory T cells (Tregs), memory T cells, and helper T cells (T_H). T_H cells and CTLs exist in  both cluster differentiation 4 and 8 (CD4 or CD8)^5,6,7
• B cells differentiate into memory cells and produce antibodies (Ab)⁶ 

How is chronic inflammation related to lymphocytosis?

Upon cellular injury, neutrophils and NKs are activated and release chemicals like cytokines and chemokines, which not only cause inflammation at the site of injury but also move the neutrophils and lymphocytes to the target inflamed region.^{6, 7} This process is called chemotaxis.² Thus, more and more movement of T cells, B cells, and neutrophils takes place from blood vessels into inflamed tissues. This whole process is called extravasation.^5,6,7

Once these immune cells reach the injured area, they again get activated by chemicals already released there, causing more release of chemokines or interleukins.⁵ This process continues and keeps activating as well as recruiting more lymphocytes, resulting in lymphocytosis.⁵ This prolongs the duration of acute inflammation, ending at chronic inflammation.^6,7 In this way, chronic inflammation causes lymphocytosis.^6,7

Mechanism of chronic inflammation at molecular levels: How lymphocytosis is linked to it

How do APCs like neutrophils entrap antigens and cause lymphocytosis?

Basophils and neutrophils present harmful substances (antigens) to major histocompatibility complex molecules (MHC) in two ways:⁸

• Attaches self-antigens to class I MHC and then  CD8 T_H cells.
• The second method is to present foreign antigens to class II MHC and then go for CD4 T_H cells

Before activation, T cells behave like naive T cells with T cell receptors (TCR), but once TCR encounters foreign antigen-MHC or self-antigen-MHC, T cells undergo differentiation into effector cells and memory cells.^7,8 Memory T cells defend the cells from subsequent attacks, whereas cytotoxic cells kill the antigens in the immediate vicinity after travelling distant distances, and T_H cells secrete cytokines, which not only kill the pathogens but also recruit more lymphocytes, leading to chronic inflammation.⁷

How does antigen-immune cell interaction occur at the molecular level?

Ligands, such as DAMPs and PAMPs, interact with pattern recognition receptors (PRRs) on APCs, which are innate immune cells. Examples of PRR include:^9,10

• IL6R or IL-1R—interleukin receptor
• Receptor for advanced glycation products (RAGE)
• Nod-like receptors (NLRP3)
• TLR 1/3/4—Toll-like receptors
• Tumor necrosis factor 𝑎 receptor—TNFR

Upon ligand-receptor interaction on APCs, multiple inflammatory pathways are activated, which include:¹⁰

• NFkB – nuclear factor kappa B activation
• Janus kinases signal transducer—JAK-STAT
• Mitogen-activated protein kinases—MAPK

These downstream pathways result in the production of multiple cytokines like IL-1, IL-6, IL-12, and TNF, which leads to pro-inflammation, more lymphocyte activation (lymphocytosis), and APC recruitment, resulting in apoptosis and cell death. ¹⁰ This leads to chronic inflammatory conditions¹⁰

How chronic inflammation lead to autoimmune conditions: The mechanism of lymphocytosis

Following are the different mechanisms that highlight the relationship between chronic inflammation and autoimmune conditions and elucidate the process of lymphocytosis in both conditions.

• Sometimes host cells resemble pathogens due to structural and functional similarities between foreign particles and self-antigenic content. It causes an activation of the immune system and outbursts of inflammatory chemicals, leading to inflammation within an immediate area of injury and killing of nearby normal cells. This process is called molecular mimicking
• Also, bacterial and viral infections lead to recruitment of macrophages, which function in antigen presentation and present a complex of viral antigens-macrophages to lymphocytes, thereby producing more pro-inflammatory cytokines. Such pro-inflammatory chemicals further stimulate the T-cell proliferation, resulting in the increase in the number of lymphocytes—lymphocytosis³
• This process causes an overkilling of infected cells alongside healthy normal cells. Here, phagocytosed cellular debris will again act as self-antigens and will be presented by APC to MHC, and then the APC-microbes-MHC complex will migrate to autoreactive CD-4 or CD8 cells. These autoreactive cells produce autoantibodies, which will again damage the neighbouring cells and prolong chronic inflammation. This process of nonspecific killing of normal cells is called bystander activation
• Furthermore, damaged cells will expose hidden antigens, which will again repeat the cycle of never-ending lymphocytosis and the resultant chronic inflammatory condition. This whole phenomenon is called epitope spreading^3,11

If this entire process is not modulated by the natural processes of central and peripheral immune tolerance, then autoreactive cells will keep damaging healthy cells and lead to overactivation of the immune system. In this way, regulatory T-cells will not be able to suppress inflammation. This will sustain a vicious cycle of chronic inflammation leading to the auto-reactivity and incessant lymphocytosis.

Therefore, chronic inflammation causes lymphocytosis, which ultimately leads to uncontrolled autoimmune destruction of cells.

Examples:

• Demyelination in Multiple Sclerosis (MS)—self-killing of oligodendrocytes and axons
• Persistent infection leads to beta cell destruction in the pancreas—diabetes mellitus
• In SLE, UV radiation damages DNA, which leads to autoantibody production against self-antigens, resulting in destruction of skin cells, joints, and kidneys by such autoimmune complexes

FAQs

Q: Among all autoimmune disorders, which prominent one exclusively leads to lymphocytosis?

A: The following disorders lead to lymphocytosis:

• Rheumatoid arthritis—RA
• Autoimmune lymphoproliferative syndrome—ALPS

Q: How does ALPS occur?

A: This is a genetic dysfunctional disorder in which Fas apoptotic pathway is  impaired, which produces more lymphocytes with no apoptosis. As a result, autoreactive CD8 and CD4 damage the body’s own tissues, thus increasing the risk of developing autoimmune disorders like SLE.¹²

Q: Does chronic inflammation cause lymphocytosis?

A: Yes, it leads to a higher number of lymphocytes—lymphocytosis.

Q: What are the symptoms of inflammation?

A: The symptoms of inflammation are as follows:

• Fever
• Reddishness on skin
• Pain in organs
• Muscle stiffness

Summary

Chronic inflammatory conditions, such as otitis media, allergic rhinitis, and asthma, and autoimmune diseases like SLE and arthritic conditions lead to more lymphocyte counts in human blood. The underlying cause is host-induced antigenic content as well as foreign entry. Antigens act as ligands (L) and need receptors (PRRs)—present on immune cells—for initiating the inflammation. L-PRR interaction triggers a signal transduction pathway and unleashes cytokines. Such pro-inflammatory chemicals recruit T-cells and B-cells (lymphocytes) for phagocytosis as well as cytotoxic action. Adaptive response only comes after initial innate immune action, and consistent inflammation produces more interleukins, leading to lymphocytosis in both CID and autoimmune conditions.