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LEUCOCYTES. Presented by Prof. Dr Gehan Sheira Tanta University 2006-2007. LEUCOCYTES. The white blood cells may be divided into two broad groups, the phagocytes and the immunocytes. The phagocytes are the granulocytes ( neutrophils-eosinophils- basophils) together with the monocytes.

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Leucocytes

LEUCOCYTES

Presented by

Prof. Dr Gehan Sheira

Tanta University

2006-2007


Leucocytes1
LEUCOCYTES

  • The white blood cells may be divided into two broad groups, the phagocytes and the immunocytes.

  • The phagocytes are the granulocytes

    ( neutrophils-eosinophils- basophils) together with the monocytes.

  • The lymphocytes (B and T) and plasma cells make up the immunocyte group.

  • Only mature phagocytes and lymphocytes are found in normal peripheral blood. Stab(band)neutrophils may occur in normal peripheral blood.

  • The role of phagocytes and immunocytes in protecting the body against infections is closely connected with tow soluble protein systems of the body,the immunoglobulins and the complement.



Leucocytes

  • Leucocytes are found in the peripheral blood as they migrate from bone marrow to the tissues.

  • The leucocytic number ( total and differential ) is remarkably constant with minor diurnal variation. 9

  • Total LC 4-8 x 10 / L

  • Diff LC Neutrophils 40- 75 %

  • Lymphocytes 20- 35 %

  • Monocytes 2 - 8 %

  • Eosinophils 1 – 4 %

  • Basophils < 1 % .

  • Polymorphonuclear granulocytes ( neutrophils – basophils – eosinophils ) with cytoplasmic granules which stain either with acid eosin or alkaline ( basic ) reactions . Monocytes and lymphocytes are mononuclear ones .


Control of granulopoiesis
-Control of granulopoiesis: from bone marrow to the tissues.

Many growth factors ( GF ) are involved :

- IL 1,3,5 for eosinophils

- IL 6,11, GMCSF , GCSF and monocytes CSF ( MCSF ) .

GFs stimulate proliferation , differentiation and function of the mature cells .

Infections increase production of GFs from T- lymphocytes and stromal cells stimulated by IL 1, TNF and endotoxin .


Clinical application of gfs
-Clinical application of GFs : from bone marrow to the tissues.

IV or SC administration of GFs(GMCSF and GCSF ) increases neutrophils , eosinophils and monocytes :

  • Severe neutropenia .

  • Severe infections as adjuvant to antimicrobial therapy .

  • Post chemotherapy , radiotherapy or BMT to decrease infections , usage of antibiotics and time in hospital .

  • Myelodysplasia to improve BM function .

  • AML to stimulate myeloid blast cells into cell cycle enhancing their sensitivity to chemotherapy .


Lymphocytes
Lymphocytes from bone marrow to the tissues.

  • Lymphocytes are the immunologically competent cells which assist the phagocytes in the defence of the body against infections and other foreign invasion .

  • Lymphoid organs : primary lymphoid organs in which lymphocytes develop are the bone marrow and the thymus , the secondary lymphoid organs in which specific immune responses are generated are the lymph nodes , spleen and lymphoid tissues of the alimentary tract and the respiratory tract .


Leucocytes

-Lymphocytes orginate from stem cell in the bone marrow : from bone marrow to the tissues.

  • Some (75 % ) migrate to the thymus where they differentiate into mature T- cells during passage from cortex to medulla .

  • T- lymphocytes are divided into helper cells

    ( CD 4 ) and suppressor or cytotoxic cells

    ( CD 8 ) .

  • Others become B – lymphocytes .

  • And few become cytotoxic or Natural killer cells .


Leucocytes

  • In BM B –lymphocytes > T-lymphocytes from bone marrow to the tissues.

  • In blood T-lymphocytes > B-lymphocytes

  • Both B and T lymphocytes respond to antigenic stimuli by transformation

  • -B-lymphocytes become plasma cells producing the immunoglobulins.Plasma cell is larger than B-lymphocyte with an eccentric round nucleus .

  • -T-lymphocytes mediate cellular immunity

  • The life span of lymphocytes may vary from few days to many years .


Lymphocytosis
Lymphocytosis from bone marrow to the tissues.

  • Causes :

    1-Infections :

  • acute :infectious mononucleosis , HIV ,herpes , mumps , hepatitis , cytomegalovirus .

  • chronic : TB , brucellosis , toxoplasmosis

    2- ALL

    3- CLL

    4- Non Hodgkin lymphoma


Lymphopenia
Lymphopenia from bone marrow to the tissues.

  • Causes :

    1-Severe BM failure with immune suppressive therapy

    2-Immune deficiency syndromes primary or secondary ( AIDS ) .


Monocytes
Monocytes from bone marrow to the tissues.

  • These derive from CFC-GM in the BM.

  • They are charecterised by irregular shape nucleus in cloudy granular cytoplasm.

  • They are motile phagocytic cells migrate into the tissues where they develop into various types of macrophages ( tissues macrophages – Kupffer cells – oesteoclasts ).


Leucocytes

-Functions of monocytes : from bone marrow to the tissues.

  • -remove debris and microorganisms by phagocytosis

  • -present antigenic material to T-lymphocytes.

  • -lysis of tumours ( tumour necrosis factor )

  • -Tumour necrosis factor ( TNF) and IL 1 produced by monocytes are considered as mediators of acute phase response.

  • Life span of monocytes lasts for months.


Monocytosis
Monocytosis from bone marrow to the tissues.

-Causes :

1 -Chronic infections ( TB , typhoid and brucellosis ).

2 -Treatment with MCSF and GMCSF.

3 -Hodgkin disease.

4 -Myelodysplasia and CMML .


Basophils
Basophils from bone marrow to the tissues.

  • -Poorly phagocytic cells

  • -Participate in hypersensitivity reaction as they possess receptors for the Fc portion of the Ig E on specific site on the cell membrane.

  • -Release of histamine occurs with degranulation of the cells.

  • -Basophils also contain heparin.

  • -Basophilic leucocytosis occurs in myeloproliferative disorders.


Eosinophils
Eosinophils from bone marrow to the tissues.

  • -T-lymphocytes appear to exert some control on eosinophils production.

  • -They are also phagocytic but less than neutrophils.

  • -Participate in hypersensitivity reactions, associated with allergic reactions and ingest antigen antibody complexes.

  • -They have a role in the containment of parasitic infections.

  • -Their numbers are severely reduced by corticosteroid therapy.


Eosinophilic leucocytosis
Eosinophilic leucocytosis from bone marrow to the tissues.

- Causes :

1-allergic and hypersensitivity diseases.

2-parasitic diseases.

3-certain skin diseases ( psoriasis……)

4-treatment with GMCSF

5-Hodgkin s disease.

6-hypereosinophilic syndrome

9

eosinophilic number is more than 1.5 x 10/L for more than 6 months with tissue damage for example heart valves , lung and skin.


Neutrophils
Neutrophils from bone marrow to the tissues.

  • Production of neutrophils takes place in the BM.

  • Mature neutrophils leave BM and circulate in the blood ( 8 hours ) then leave the circulation by adhering to capillary endothelium ( margination ) and migrate through the vessel wall into the tissues where they function. A considerable proportion of neutophils in blood is marginated.

  • -Stress factors ( infection – emotion – exercise ) may return these cells to circulation raising the leucocytic count .


Leucocytes

  • -Life span of neutrophils is about 3- 4 days . from bone marrow to the tissues.

  • -Immature forms ( myelocytes ) are found in the blood when production of leucocytes is being stimulated (severe pyogenic infection ) .

  • More primitive forms ( myeloblasts ) appear in the blood indicating a serious disturbance of marrow function as in leukemia and invasion of BM by metastases .

  • -A particularly marked neutrophilia may be termed leukaemoid reaction and may be seen in life threatening infection , some cancers and severe haemolysis .


Leucocytes

  • -It may be impossible to distinguish chronic myeloid leukaemia from a leukaemoid reaction on the blood count alone , but on the demonstration of a decreased neutrophil alkaline phosphatase score ( NAP : 20- 100 ) and the presence of Phladelphia chromosome on analysis of BM .


Function of neutrophils
Function of neutrophils leukaemia from a leukaemoid reaction on the blood count alone , but on the demonstration of a decreased neutrophil alkaline phosphatase score ( NAP : 20- 100 ) and the presence of Phladelphia chromosome on analysis of BM .

  • -Neutrophils are phagocytic cells which ingest bacteria and fungi . They are attracted to bacteria by chemotaxis and phagocytosis is increased by opsonization stimulated by Igs and complement as phagocytic cells have Fc and C3b receptors .

  • -Engulfed bacteria are destroyed by neutrophils lysosomes and enzymes .

  • -Autodigestion is a potent stimulant to fresh neutrophils formation and pyrogens are released .


Leucocytes

  • -Neutrophils also ingest uric acid crystals and may disintegrate liberating tissue damage substances causing local inflammation .

  • -Neutrophils can produce vitamin B12 binding protein ( transcobalamin 111 ) . So , the increased level of B12 vitamin in serum in CML .


Neutrophil leucocytosis
Neutrophil leucocytosis disintegrate liberating tissue damage substances causing local inflammation .

-Causes :

1- Bacterial infection ( pyogenic ).

2- Inflammation and tissue necrosis .

3- Neoplasms .

4- Acute haemorrhage and haemolysis .

5- Metabolic disorders ( uremia – gout

-acidosis ) .

6-Treatment with GFs .

7- Myeloproliferative disorders .

8- Corticosteroid therapy as it inhibits

migration .


Leucocytes

- With neutrophil leucocytosis : disintegrate liberating tissue damage substances causing local inflammation .

  • Fever with release of leucocyte pyrogen

  • Shift to the left with increased stab forms

  • Increase of the NAP score .


Neutropenia
Neutropenia disintegrate liberating tissue damage substances causing local inflammation .

  • Neutropenia exists when the absolute neutrophil count falls below 1500/ul . Agranulocytosis occurs

  • with complete absence of neutrophils in the peripheral blood

  • The neutropenic patient is increasingly vulnerable to infection by gram +ve and gram –ve bacteria and by fungi . The risk of infection is related to the severity of neutropenia .


Causes of neutropenia
Causes of neutropenia disintegrate liberating tissue damage substances causing local inflammation .

  • All the causes of pancytopenia and aplastic anaemia may cause neutropenia. Isolated neutropenia and agranulocytosis are often due to an

  • idiosyncratic reaction to drugs or exposure to a variety of chemicals .

  • -Infections : -Viral , e.g. hepatitis, HIV, glandular fever.-Bacterial , e.g. miliary TB, typhoid, brucellosis.


Drugs induced
-Drugs induced : disintegrate liberating tissue damage substances causing local inflammation .

-Antibiotics : sulphonamides –chloramphenicol co-trimoxasole .

-NSAIDs : phenylbutazone ….

-Anticonvulsants : phenytoin ….

-Antithyroids : carbimazol ….

-Antidiabetics : chlorpromide ….

-Antihypertensive : captopril ….

- Antiarrhythmic : procainamide ….

- Antimalarial : chloroquine …

- Miscellaneous : gold, penicillamine ….


Leucocytes

  • -Bone marrow infiltration or replacement, e.g.leukaemia , lymphoma, myeloma and carcinoma .

  • -Immune : autoimmune , SLE , Felty s syndrome

  • -Hypersplenism .

  • -Congenital neutropenia ,Kostmann s syndrome,is a AR disease presenting in the first year of life with life-threatening infections .

  • -Cyclic neutropenia , it is a rare syndrome with 3-4 week periodicity , severe but temporary .


Clinical picture
Clinical picture lymphoma, myeloma and carcinoma .

  • Severe neutropenia is particularly associated with infections of the mouth and throat .Painful and often intractable ulceration may occur at these sites .Septicaemia rapidly supervenes . Cellulitis and pneumonia are common .

  • With severe neutropenia , the usual signs of inflammatory response to infection may be absent .

  • Treatment :

    - Treatment of the cause ,drug discontinuation.

    - Combination of broad spectrum antibiotics .

    - Myeloid growth factors may be of help

    ( GCSF – GMCSF ) .


Immunoglobulins
Immunoglobulins lymphoma, myeloma and carcinoma .

  • These are heterogeneous group of proteins produced by plasma cells . They are divided into five subclasses or isotypes : Ig G , Ig A , Ig M , Ig E and Ig D . Ig G is the common contributes of the normal serum immunoglobulin ( about 80 % ) and is further subdivided into four subclasses : Ig G 1 , G 2, G 3 and G 4 . Ig A is the main Ig in secretions , it is subdivided into to types . Ig M has the largest molecular weight . Ig D and E are involved in delayed hypersensitivity reactions .


Leucocytes

The Igs are all made up of the same basic lymphoma, myeloma and carcinoma .structure , consisting of two heavy chains which are called gamma in Ig G , alpha in Ig A , mu in Ig M , delta in Ig D and epsilon in Ig E , and two light chains ( Kappa or Lambda ) which are common to all five Igs . They can be broken into a constant Fc fragment and two highly variable Fab fragments .


Leucocytes

  • The main role of Igs is defence against foreign organisms . They have a vital role in the pathogenesis of a number of haematological disorders :

  • - Secretion of a specific Ig from a monoclonal population of plasma cells occurs in macroglobulinaemia and most cases of multiple myeloma .

  • –Bence Jones protein found in the urine in some cases of multiple myeloma consists of a monoclonal secretion of light chains or light chain fragments .

  • – Igs may bind to blood cells in a variety of immune disorders and cause agglutination or destruction of cells .


Multiple myeloma
Multiple Myeloma They have a vital role in the pathogenesis of a number of haematological disorders :

  • It is a malignant disorder of plasma cells . Plasma cells are derived from B-lymphocytes by transformation after exposure to antigenic stimuli . Plasma cells manufacture Igs with only one type of light chain ( Kappa or Lambda ).

  • In myeloma and other malignant disorders of B-lymphocytes , all the malignant cells produce the same Ig which indicates that the tumour is derived originally from one cell cloning

    ( monoclonal ).


Leucocytes

  • The monoclonal Ig is called a paraprotein and appears on serum electrophoresis as clear cut band . In myeloma , the paraprotein produced belongs to one of the five Igs and has one or other of the two light chains .

  • Bence Jones proteinuria appears in patients with multiple myeloma when only part of the Ig molecule is produced by the tumour cells, most commonly the light chains .


Pathology and clinical features
Pathology and clinical features serum electrophoresis as clear cut band . In myeloma , the paraprotein produced belongs to one of the five Igs and has one or other of the two light chains .

  • -Multiple myeloma is a neoplastic proliferation of plasma cells , more common in males with a peak incidence between 60 and 70 years .

  • - It is charecterised by replacement of the BM by the malignant cells leading to anemia and later to general BM failure.

  • -IL6 is a potent growth factor for myeloma by an autocrine mechanism.

  • -Osteoclastic stimulation with absorption of bone resulting in diffuse osteoporosis , bone pain , lytic lesions and pathological fractures .


Leucocytes

  • -Hypercalcemia is common and appears to be mediated by osteoclast activating factor ( OAF ) and similar lymphokines ( IL1, TNF ) causing thirst , lethary , polyuria , anorexia , vomiting and constipation .

  • -Malignant plasma cells can form solitary tumour plasmacytoma either in tissue or bone causing spinal cord compression .

  • -Excessive production of the paraproteins may cause hyperviscosity syndrome ( mucosal bleeding , vertigo , headache , visual disturbances , stupor and coma ) .


Leucocytes

  • -Light chain components of Igs may cause renal failure aggravated by hypercalcemia , or may be deposited in tissues as amyloid leading to amyloidosis renal damage .

  • -Myeloma patients are prone to recurrent infections due to failure of antibody production , neutropenia and the effects of chemotherapy . Respiratory infections especially with H.influenza and streptococcus pneumonia .

  • -Abrormal bleeding tendency as myeloma protein may interfere with platelet function and coagulation factors , thrombocytopenia occurs in advanced disease .


Diagnosis and investigations
Diagnosis and investigations aggravated by hypercalcemia , or may be deposited in tissues as amyloid leading to amyloidosis renal damage .

-Detection of paraprotein ( monmclonal Igs or light chains in serum or urine by serum protein or immune electropheresis.


Leucocytes

  • -Infiltration of BM by abnormal plasma cells usually > 20 % .

  • -Osteoporosis and osteolytic bone lesions

    ( skull , spine , ribs and proximal long bones ).

  • -Hypercalcemia , high ESR , anaemia , neutropenia and thrombocytopenia in advanced disease .

  • -Serum urea and creatinine are raised in 20 % of cases . Serum B2-microglobulin is a useful indicator of prognosis .

  • -On occasion the abnormal protein in urine is cryoprecipitable .


Treatment
-Treatment: .

  • -At early stage of the disease , with no symptoms, no specific treatment only observe the patients.

  • -All patients must drink at least 3lit. fluid daily that may completely reserve renal impairment and help to manage hypercalcemia with IV 90 mg of bisphosphonates monthly .

  • -Melphalan ( 7mg/m2 for 4 days every 4-6 weeks ) in combination with prednisolone may be effective in bringing the disease under control .


Leucocytes

  • -Recently , in patients less than 60 years , more intensive combination chemotherapy is used such as C-VAM protocol ( cyclophosphamide , vincristine , adriamycin and methylprednisolone. )

  • -Following several cycles of treatment most patients proceed to autologous stem cell transplantation ( SCT ) . Most patients unfortunately are not young enough to undergo allogenic transplantation .


Leucocytes


Infectious mononucleosis
Infectious Mononucleosis chemotherapy or transplantation . Thalidomide is showing promise in relapsed disease .

  • It is an acute infectious disease due to Epstein-Barr virus.

  • The disease is charecterised by a lymphocytosis caused by clonal expansions of T-cells reacting against B-

  • lymphocytes infected with EBV.

  • It may occur at any age but usually occurs between 10 and 35 years.

  • The virus infects and replicates in B-lymphocytes and is shed in the throat. So, transmission is usually by oral contact possibly by saliva.

  • The incubation period is 7 to 15 days.


Clinical features
-Clinical features: chemotherapy or transplantation . Thalidomide is showing promise in relapsed disease .

  • Toxic manifestations early in the disease, malaise, tiredness, headache, anorexia, myalgia and fever.

  • Lymphadenopathy, discrete, non suppurative slightly painful esp. along posterior cervical chain.

  • Splenomegaly in about 50% of cases and hepatomegaly in about 15%.

  • Sore throat with exudative tonsillitis is usually present.

  • Maculopapular or occasionally petechial rash especially if ampicillin has been given.


Complications
-Complications: chemotherapy or transplantation . Thalidomide is showing promise in relapsed disease .

  • 1- Haemolytic anemia, thrombocytopenia.

  • 2- Hepatitis, jaundice, rupture spleen.

  • 3- Aseptic meningitis and CNS involvement.

  • 4- Chronic fatigue syndrome.


Investigations
-Investigations: chemotherapy or transplantation . Thalidomide is showing promise in relapsed disease .

  • Predominance of atypical lymphocytes in the peripheral blood( larger than normal, vacuolated foamy cytoplasm, dark chromatin in the nucleus).

  • Hetrophile agglutination test, high titres occur during the second and third weeks. Hetrophile antibodies against sheep red cells form the basis of the Paul-Bunnell test, and against horse red cells instead in the monospot test.

  • Specific antibody to the EBV nuclear antigen.

  • Autoimmune haemolytic anaemia, and thrombocytopenia are frequent


Treatment1
-Treatment: chemotherapy or transplantation . Thalidomide is showing promise in relapsed disease .

  • Symptomatic: rest, aspirin, NSAIDs, warm saline throat irrigations.

  • 5 day course of corticosteroids, prednisolone 50 mg/day for 3 days with tapering may be of beneficial.

  • Antiviral drugs are not helpful although newer agents( famciclovir ) appear to have anti EBV properties.

  • Treatment of complications.