Lymphocytosis

Lymphocytosis: > 33%

Etiology

• Acute viral infections (e.g., rubella, infectious mononucleosis, mumps)
• Chronic bacterial infections
  • Bordetella pertussis (Whooping cough)
    • Often causes marked lymphocytosis, particularly in children
    • Can elevate lymphocyte counts to 20,000-30,000/μL or higher
  • Mycobacterium tuberculosis
    • Chronic TB infection can produce lymphocytic responses
    • More common in the later stages of infection
  • Brucella species (Brucellosis)
    • Often presents with relative lymphocytosis
  • Treponema pallidum (Syphilis)
    • Secondary and tertiary syphilis can produce lymphocytosis
  • Borrelia burgdorferi (Lyme disease)
    • Can cause lymphocytosis, especially in later stages
  • Mycoplasma pneumoniae
    • Often associated with atypical lymphocytes
• Neoplasia (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, CLL)

Tip

The lymphocyte count may be increased or decreased in lymphoma.

T cell

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T cell activation

1. APC ingests and processes antigen, then migrates to the draining lymph node.
2. T-cell activation (signal 1): exogenous antigen is presented on MHC II and recognized by TCR on Th (CD4+) cell. Endogenous or cross-presented antigen is presented on MHC I to Tc (CD8+) cell.
3. Proliferation and survival (signal 2): costimulatory signal via interaction of B7 protein (CD80/86) on dendritic cell and CD28 on naïve T cell.
   • Antigen presentation without this co-stimulatory signal will lead to T-cell anergy:
     • Important self-tolerance mechanism
     • The cell will not be activated even though it is exposed to its antigen
   • Superantigens (e.g., toxic shock syndrome toxin 1, enterotoxin B) link MHC II antigen-presenting cells and T-cell receptors on T cells and lead to activation of T cells without a costimulatory signal.
4. Activated Th cell produces cytokines. Tc cell able to recognize and kill virus-infected cell.

T cell differentiation

Cell	Induced by	Inhibited by	Secretes
Th1	IFN-γ, IL-12	IL-4, IL-10	IFN-γ, IL-2
Th2	IL-2, -4	IFN-γ	IL-4, -5, -6, -10, -13
Th17	IL-1, -6, TGF-β	IFN-γ, IL-4	IL-17, -21, and -22
Treg	TGF-β, IL-2	IL-6	TGF-β, IL-10, -35

T-cell development

• Positive selection of T cells: ensures that the thymus produces functional T cells
  • Location: thymic cortex
  • Thymic cortical cells express MHC class I and MHC class II antigens.
  • Tests if T-cell receptors can bind to MHC appropriately (not too strongly or too weakly)
    • T cells (CD4+/CD8+, double-positive thymocytes) receive survival signal.
    • Dysfunctional T cells then undergo apoptosis.
• Negative selection of T cells: ensures that the thymus does not produce self-reacting T cells
  • Location: thymic medulla
  • Tests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cells
    • T cells that do not bind receive survival signal.
    • T cells that bind self-antigens undergo apoptosis, except for a few that become regulatory T cells.
  • Self-antigen presentation is mediated by the autoimmune regulator protein (AIRE protein), dysfunction of which can lead to:
    • Adrenal insufficiency
    • Chronic mucocutaneous candidiasis
    • Hypoparathyroidism

T-cell subtypes

Cytotoxic T cells (killer T cells)

• Surface markers: CD8
• Function: Important component of cell-mediated immunity; recognize and kill cells infected with intracellular pathogens (especially viruses) and neoplastic cells; interact with foreign antigens presented via MHC I; induce apoptosis or cell lysis of presenting cells
• Stimulated by: Macrophages
• Clinical significance: HIV, Hepatitis B, Adult T cell lymphoma

T-helper cells (Th cells)

Th1 cells

• Surface markers: CD4, CD40L
• Function: Promote cellular immune response; fight intracellular pathogens
• Stimulate: Macrophages, Cytotoxic T cells, NK cells, B cells (leading to IgG production)
• Clinical significance: Infections with intracellular pathogens (e.g., Mycobacteria, Salmonella), IL-12 receptor deficiency, Type I diabetes, Rheumatoid arthritis, Multiple sclerosis

Th2 cells

• Function: Initiate humoral immune response in cooperation with B lymphocytes; fight extracellular pathogens (especially parasites)
• Stimulate: Eosinophils, Mast cells, Basophils, B cells (leading to IgE production)
• Clinical significance: Helminth infections, Type 1 hypersensitivity (asthma, allergic rhinitis)

Th17 cells

• Function: Regulate tissue inflammation (both proinflammatory and antiinflammatory effects); fight extracellular pathogens
• Stimulate: Neutrophils
• Clinical significance: Hyper IgE syndrome

Regulatory T cells (Treg, suppressor T cells)

• Surface markers: CD4, CD25
• Function: Limit and protect against excessive immune response; promote immune self-tolerance; prevent formation of autoantibodies
• Stimulate/suppress: CD4+ and CD8+ T effector cells
• Clinical significance: sIPEX syndrome

B cell

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B cell activation and class switching

1. Th-cell activation as above.
2. B-cell receptor–mediated endocytosis.
   • B lymphocytes recognize antigens via their B-cell receptors (membrane‑bound immunoglobulins, IgD or IgM) → B cell receptor-mediated endocytosis of the BCR/antigen complex → breakdown of antigen into small fragments by lysosomal proteases → presentation of antigen fragment via MHC class II receptors on B cell surface to Th cells plus costimulation of B cell CD40 receptor by Th cell CD40L → T cell‑dependent activation of B cells (plasma cells) → immunoglobulin production
   • B cell and T cell need to be activated by the same antigen
3. Exogenous antigen is presented on MHC II and recognized by TCR on Th cell.
4. CD40 receptor on B cell binds CD40 ligand (CD40L) on Th cell.
5. Th cells secrete cytokines that determine Ig class switching of B cells.
   • Th1 (IFN-γ), Th2 (IL-4), Tfh (IL-21), Th17 (IL-21): stimulates class switching to IgG.
   • Th2 (IL-4, IL-13): stimulate class switching to IgE.
   • Th2 (IL-5) + Treg (TGF-β): stimulate class switching to IgA.
6. B cells are activated and produce IgM. They undergo class switching and affinity maturation.

Lymphatic system

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Lymph nodes

Function

• Nonspecific lymph filtration: macrophages within lymph node
• Storage and circulation of B cells and T cells
• Immune system activation: Antigen presentation induces differentiation and proliferation of B lymphocytes and activation of T lymphocytes.

Structure

Histology

• Cortex (B-cell zone): contains lymphoid follicles, which is the site of B lymphocyte storage, differentiation, and proliferation
  • Secondary lymphoid follicle (active): dense mantle zone surrounding a pale germinal center
  • Primary lymphoid follicle (inactive): dense aggregates of naive B lymphocytes
• Paracortex (T-cell zone)
  • Region between the cortex and medulla
  • Contains T lymphocytes and high endothelial venules, which allows circulating B and T lymphocytes to enter or leave the bloodstream
  • Site of T-cell activation
• Medulla
  • Medullary cords: tightly packed with plasma cells and lymphocytes
  • Medullary sinus of the lymph node
    • Composed of macrophages, reticular cells
    • Connected to the efferent lymphatic structures

Clinical significance

• Inflammatory or immune reactions (e.g., due to EBV infection) → reactive paracortical hyperplasia → clinically apparent lymphadenopathy
• Depletion of paracortical lymphocytes: DiGeorge syndrome

NK cells

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• Surface markers
  • Fc receptor (CD16): a membrane receptor protein that recognizes and binds to antibodies that have attached to pathogens
    • Mediates a phagocytic and/or cytotoxic response
    • Found on many immune cells, e.g., NK cells, neutrophils, and macrophages
  • CD56: a neural cell adhesion molecule specific to NK cells

Mnemonic

CD16 for NK cells because when 16 year olds get their driver’s licenses they become killers, naturally.