Lymphocytes

LYMPHOCYTES

1. By - dr. mahima tyagi pg ii year LYMPHOCYTES

2. CONTENTS Introduction Classification T cell maturation B cell maturation Null cells or NK cells Disorders of lymphocytes Effect of drugs on lymphocytes References

3. INTRODUCTION Immune system produces antibody and cells that deactivate pathogens. SO, protect the body from infection by microorganisms, assist in healing, remove or repair damaged cells if an infection or injury occur

4. LYMPHOCYTES .These are the key cells of immune system. They specifically recognize individual pathogens. Vary both in size & morphology.

5. Lymphocytes are small, round cells found in peripheral blood, lymph, lymphoid organs and in many other tissues. In peripheral blood, they constitute 20-45% of the leucocyte population, while in lymph and lymphoid organs they form the predominant cell type.

6. The human body contains about 10 12 lymphocytes, approximately 10 9 of them being renewed daily. Only about 1% of the total body lymphocytes are present in the blood.

7. CLASSIFICATION According to their size ,lymphocytes can be classified into small (5-8 µm),medium (8-12 µm), and large (12-15 µm)lymphocytes . Small lymphocytes are most numerous.

8. Depending on their life-span ,they can be classified as short lived and long lived lymphocytes. In human beings ,the short lived lymphocytes have a life span of about 2 weeks, while the long lived cells may last for 3 years or more, or even for life.

9. Short lived lymphocytes are the effector cells in immune response, while the long lived cells act as the storehouse for immunological memory. Long lived cells are mainly thymus derived.

10. Lymphopoeisis takes place mainly in the central lymphoid organs where they differentiate and mature before entering the circulation and then the peripheral lymphoid organs and tissues like a policeman on beat patrol.

11. These populations of lymphocytes do not remain distinct but mix together in a process known as “ lymphocyte recirculation” . There is a constant traffic of lymphocytes through the blood, lymph, lymphatic organs and tissues. . Recirculating lymphocytes are mainly T cells .

12. A lymphocyte has been “educated” by the central lymphoid organs becomes an ‘immunologically competent cell’ (ICC). Mature T and B cells, before they encounter antigens are called naive cells . Such cells, though not actually engaged in immunological response, are nevertheless fully qualified to undertake such a responsibility when appropriately stimulated by an antigen.

13. FUNCTIONS

14. Recognition of antigens Lymphocytes have antigen recognition mechanisms on their surface ,enabling each cell to recognize only one antigen. The reaction of an immunocompetent cell to its specific antigen may be induction of either ‘tolerance’ or the immune response .

15. Stimulated T cells produce certain activation products ( lymphokines ) and induce CMI, while stimulated B cells divide and transform into plasma cells which synthesise immunoglobulins .

16. A number of surface antigens or markers have been identified on lymphocytes and other leukocytes by means of monoclonal antibodies. These markers reflect the stage of differentiation and functional properties of the cells.

17. When a cluster of monoclonal antibodies was found to react with a particular antigen, it was defined a separate marker and given a CD number .Over 150 CD markers have been identified so far. The most clear cut differentiation between T and B cells is by their surface markers,e.g ., by demonstration of CD3 on T cells and Ig on B cells.

18. T- Cell Maturation T cell precursors from yolk sac, fetal liver and bone marrow migrate to the thymus during the embryonic and post natal stages. The earliest identifiable cells of T lineage are the CD7 pro-T cells which acquire CD2 on entering the thymus. They synthesise CD3 in the cytoplasm and become pre- T cells.TCR synthesis also takes place.

19. T cells also develop MHC restriction so that CD8 cells respond only to foreign antigens presented along with HLA class I, and CD4 cells to those presented with HLA Class II molecules. TCR occurs as two pair of glycoprotein chains, either α β or ϒδ .

20. The function of δ TCR cells is not well understood, but they are believed to be immune survelliance cells on epithelial surfaces and a form of defense against intracellular bacteria. Sequential antigenic changes characterising T cell maturation enable their easy identification.

21. Acute T cell malignancies such as lymphoblastic leukemia and lymphomas involve early Tcells , pro Tcells and other immature forms. Chronic Tcell malignancies like mycosis fungoides , peripheral Tcell lymphomas and HTLV-1 associated adult Tcell leukaemias involve mature Tcells , mainly CD4 cells.

22. B cell maturation B lymphocyte precursors, pro B-cells , develop in the fetal liver during embryonic life and in the bone marrow afterwards continuously throughout life. Rearrangement of immunoglobulin gene takes place on their pre-B cells, which synthesize cytoplasmic Ig M.

23. Next immature B cells- Ig M is expressed on the cell surface. These cells migrate to the periphery and undergo immunoglobulin isotype switching so that instead of IgM alone ,cell expresses IgD as well as IgM , IgG,IgA or IgE .

24. On contact with its appropriate antigen , the mature B cell undergoes clonal proliferation. Some activated B cells become long lived memory cells responsible for the recall phenomenon seen on subsequent contact with same antigen. The majority of activated B cells are transformed into plasma cells .

25. Plasma cells are end cells and have a short lifespan of two or three days. A plasma cell makes an antibody of a single specificity , of a single immunoglobulin class allotype and of single light chain type only.

26. They secrete low affinity polyreactive IgM antibodies, many of them autoantibodies . They are responsible for the T –independent ‘natural’ IgM antibacterial antibodies which appear in neonates seemingly without antigenic stimulus.

27. NULL CELLS When circulating lymphocytes are classified by their surface markers into T and B cells , about 5-10% of the cells are found to lack features of either type. They were called null cells . Because of their morphology ,they are also known as large granular lymphocytes (LGL).

28. They are nearly double the size of the small lymphocytes,with indented nuclei and abundant cytoplasm containing several azurophilic granules,composedof mitochondria,ribosomes,endoplasmic reticulum and Golgi apparatus.

29. LGL are heterogenous group of cells with differences in their functional and surface marker features. The most important member of this group is the natural killer cells. NK cells account for up to 15% of blood lymphocytes. Functional NK cells are found in spleen.

30. Natural killer cell possess spontaneous cytotoxicity towards various target cells, mainly malignant and virus infected cells . The functional activity of NK cells is regulated by a balance between signals from activating and inhibitory receptors

31. ROLE OF LYMPHOCYTES B cells are responsible for the humoral arm of the adaptive immune system, and thus act against extracellular pathogen.

32. T cells are responsible for the cell –mediated arm of the adaptive immune response, and are mainly concerned with cellular immune response to intracellular pathogens such as viruses.

33. Some of T cells are involved in the control of B cell development and antibody production another group of T cells interacts with phagocytic cels to help them destroy pathogens they have taken up. a third set of T cells recognized cells infected by virus and destroys them.

34. DISORDERS OF LYMPHOCYTES

35. REACTIVE DISORDER OF LYMPHOCYTES

36. LYMPHADENTIS Following their initial development from precursors in the bone marrow (B cells) and the thymus (T cells), lymphocytes circulate through the blood and, under the influence of specific cytokines and chemokines , home to lymph nodes, spleen, tonsils, adenoids, and Peyer's patches, which constitute the peripheral lymphoid tissues.

37. Lymph nodes, the most widely distributed and easily accessible lymphoid tissue, are frequently examined for diagnostic purposes. They are discrete encapsulated structures that contain well-organized B-cell and T-cell zones, which are richly invested with phagocytes and antigen-presenting cells.

38. The activation of resident immune cells leads to morphologic changes in lymph nodes . Within several days of antigenic stimulation, the primary follicles enlarge and are transformed into pale-staining germinal centers , highly dynamic structures in which B cells acquire the capacity to make high-affinity antibodies against specific antigens.

39. Trivial injuries and infections induce subtle changes, while more significant infections inevitably produce nodal enlargement and sometimes leave residual scarring. For this reason, lymph nodes in adults are almost never “normal” or “resting,” and it is often necessary to distinguish morphologic changes secondary to past experience from those related to present disease.

40. Acute Nonspecific Lymphadenitis Acute lymphadenitis in the cervical region is most often due to microbial drainage from infections of the teeth or tonsils, while in the axillary or inguinal regions it is most often caused by infections in the extremities. Acute lymphadenitis also occurs in mesenteric lymph nodes draining acute appendicitis.

41. Unfortunately, other self-limited infections may also cause acute mesenteric adenitis and induce symptoms mimicking acute appendicitis, a differential diagnosis that plagues the surgeon. Systemic viral infections (particularly in children) and bacteremia often produce acute generalized lymphadenopathy

42. Chronic lymphadenitis is particularly common in inguinal and axillary nodes, which drain relatively large areas of the body and are challenged frequently.

43. LYMPHOID NEOPLASMS The current World Health Organization (WHO) classification scheme uses morphologic, immunophenotypic , genotypic, and clinical features to sort the lymphoid neoplasms into five broad categories,which are separated according to the cell of origin

44. -- The WHO Classification of the Lymphoid Neoplasms I . PRECURSOR B-CELL NEOPLASMS B-cell acute lymphoblastic leukemia /lymphoma (B-ALL) II. PERIPHERAL B-CELL NEOPLASMS Chronic lymphocytic leukemia /small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic and nodal marginal zone lymphomas Extranodal marginal zone lymphoma Mantle cell lymphoma Follicular lymphoma Marginal zone lymphoma Hairy cell leukemia Plasmacytoma /plasma cell myeloma Diffuse large B-cell lymphoma Burkitt lymphoma

45. III. PRECURSOR T-CELL NEOPLASMS T-cell acute lymphoblastic leukemia /lymphoma) IV. PERIPHERAL T-CELL AND NK-CELL NEOPLASMS T-cell prolymphocytic leukemia Large granular lymphocytic leukemia Mycosis fungoides / Sézary syndrome Peripheral T-cell lymphoma, unspecified Anaplastic large-cell lymphoma Angioimmunoblastic T-cell lymphoma Enteropathy -associated T-cell lymphoma Panniculitis -like T-cell lymphoma Hepatosplenic γδ T-cell lymphoma Adult T-cell leukemia /lymphoma Extranodal NK/T-cell lymphoma NK-cell leukemia

46. V. HODGKIN LYMPHOMA Classical subtypes Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depletion

47. The vast majority (85% to 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumors ; only rarely are tumors of NK cell origin encountered . Most lymphoid neoplasms resemble some recognizable stage of B- or T-cell differentiation .

48. Acute Lymphoblastic Leukemia /Lymphoma Acute lymphoblastic leukemia /lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts . About 85% are B-ALLs, which typically manifest as childhood acute “ leukemias .” ; The less common T-ALLs tend to present in adolescent males as thymic “lymphomas.”

49. Approximately 5,000 cases are diagnosed annually with 2/3ds in children. ALL is almost three times as common in whites as in blacks, and slightly more frequent in boys than in girls. Hispanics have the highest incidence of any ethnic group. B-ALL peaks in incidence at about the age of 3.Similarly the peak incidence of T-ALL is in adolescence.

50. Oral manifestations Marrow failure results in thrombocytopenia manifested by petechial skin and posterior palate hemorrhages and gingival bleeding, gingival infiltration by leukemic cells and gingival ulcerations as a result of infection by normal oral flora

51. Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) These two disorders differ only in the degree of peripheral blood lymphocytosis . Most affected patients have sufficient lymphocytosis to fulfill the diagnostic requirement for CLL (absolute lymphocyte count >4000 per mm 3 ). CLL is the most common leukemia of adults in the Western world.

52. There are about 15,000 new cases of CLL each year in the United States. The median age at diagnosis is 60 years, and there is a 2 : 1 male predominance. In contrast, SLL constitutes only 4% of NHLs. CLL/SLL is much less common in Japan and other Asian countries than in the West.

53. Oral manifestations Oral manifestations at presentation of CLL are infrequent and generally related to bleeding. The oral lesion rate increases once chemotherapy is initiated for treatment. The most common being exfoliative chelitis and infection with herpes and Candida,followed by hemorrhagic lesions and mucositis .

54. Follicular Lymphom a Follicular lymphoma is the most common form of indolent NHL in the United States, affecting 15,000 to 20,000 individuals per year. It usually presents in middle age and afflicts males and females equally. It is less common in Europe and rare in Asian populations. The tumor likely arises from germinal center B cells and is strongly associated with chromosomal translocations involving BCL2 .

55. Burkitt Lymphoma ( 1) African (endemic) Burkitt lymphoma, (2) sporadic ( nonendemic ) Burkitt lymphoma, and (3) a subset of aggressive lymphomas occurring in individuals infected with HIV. Burkitt lymphomas occurring in each of these settings are histologically identical but differ in some clinical, genotypic, and virologic characteristics.

56. Clinical Features. Both endemic and sporadic Burkitt lymphomas are found mainly in children or young adults; Most tumors manifest at extranodal sites . Endemic Burkitt lymphoma often presents as a mass involving the mandible and shows an unusual predilection for involvement of abdominal viscera, particularly the kidneys, ovaries, and adrenal glands.. Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy. Most children and young adults can be cured. The outcome is more guarded in older adults.

57. Clinically evident jaw tumors may result in tooth mobility and pain, intraoral swelling of mandible and maxilla and anterior open bite. Radiographic features show resorption of alveolar bone,loss of lamina dura ,enlargement of tooth follicles and “teeth floating in air” appereance .

58. Plasma Cell Neoplasms and Related Disorders These B-cell proliferations contain neoplastic plasma cells that virtually always secrete a monoclonal Ig or Ig fragment . Collectively, the plasma cell neoplasms (often referred to as dyscrasias ) account for about 15% of the deaths caused by lymphoid neoplasms . The most common and deadly of these neoplasms is multiple myeloma, of which there are about 15,000 new cases per year in the United States.

59. Multiple Myeloma Multiple myeloma is a plasma cell neoplasm characterized by multifocal involvement of the skeleton . Although bony disease dominates, it can spread late in its course to lymph nodes and extranodal sites such as the skin. Multiple myeloma causes 1% of all cancer deaths in Western countries. Its incidence is higher in men and people of African descent. It is chiefly a disease of the elderly, with a peak age of incidence of 65 to 70 years.

60. Oral manifestations Patients with MM manifests soft tissue masses that are extramedullary plasmablastic tumors of jaw .

61. Initial signs involve paresthesia of the inferior alveolar nerve and mental nerves,swelling , tooth mobility and radiolucency.Typical feature being the “ punched out “ lesions in skull .

62. Lymphoplasmacytic Lymphoma. Lymphoplasmacytic lymphoma is a B-cell neoplasm of older adults that usually presents in the sixth or seventh decade of life. Although bearing a superficial resemblance to CLL/SLL, it differs in that a substantial fraction of the tumor cells undergo terminal differentiation to plasma cells.

63. Hodgkin Lymphoma Hodgkin lymphoma (HL) encompasses a group of lymphoid neoplasms that differ from NHL in several respects. While NHLs frequently occur at extranodal sites and spread in an unpredictable fashion, HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues . For this reason, the staging of HL is much more important in guiding therapy than it is in NHL. HL also has distinctive morphologic features.

64. Non Hodgkins Lymphoma NHL is known to be associated with chronic inflammatory diseases such as sjogren’s syndrome, celiac disease and rheumatoid arthritis and immune suppression from HIV and medications to patient who received solid organ transplantation. Clinically as lymphodenopathy and sometimes extranodal involvement of the git,skin,bone marrow,sinuses,thyroid ,CNS.

65. Diagnosis of NHL in the oral cavity may result from gingival or mucosal tissue swelling or masses .symptoms may include anesthesia or paraesthesia .presentation can also include non healing ulceration with ill defined borders in surrounding mucosa .

66. Effect of drugs on the T and B cells Steroid treatment causes circulating lymphocytopenia , which is maximal at 4-6 hours and returns to normal by 24 hrs. T cells are affected more, and within them CD4 are more depleted than CD8 .

67. Cyclophosphamide mainly affects lymphocyte numbers and function, particularly after low dose daily oral therapy.Bcells are reduced more than T cells. Since it inteferes with both Tand Bcell it is effective in controlling both antibody mediated and cell mediated immune responses in experimental animals and humans thus can be used in management of Autoantibody- mediated disease Allograft rejection

68. Mycophenolate blocks both T and B cell proliferative responses in doses that appear to have no effect on other cell types.it also inhibits glysosylation of adhesion molecules involved in leukocyte traffic, thus restriciting amplification of inflammatory injury.

69. Lymphoid tissues are damaged by nutrient deficiencies. Lymphoid atropy is a prominet morphological feature of malnutrition. Protein energy malnutrition affects cell mediated immunity and phagocytosis . Iron deficiency is associated with impaired NK cell activity.

70. Referrences Burket’s oral medicine, 11 th edition Immunology, 7 th edition- Roitt,Brostoff Robbins and Cotran – Pathologic basis of disease, 8th edition R Ananthanarayan & CKJ Paniker Text book of Microbiology; 6 th Edition: Ch 15 Structure & Functions of Immune system