Hematology

1. Macrophage in Health and
Disease

2. Contents
 Introduction
 Development and Differentiation
 Role in health
 Macrophages in disease
 Chronic infections
 Atherosclerosis
 Malignancies
 Chronic inflammatory diseases
 Diseases of Macrophages:Histiocytic disorders

3. Introduction
 Elie Metchnikoff:- Phagocytic cells
 Aschoff:-Reticuloendothelial System
 Origin
 Phylogeny:primitive protozoa
 Ontogeny:-Yolk sac
 Produced as monocytes in bone marrow
 Differentiate in tissues

4. Development

5. Differentiation
Surface lectins
ECM components
Fibronectin
Laminin
Mediated via NF-γ

6. Morphology

7. Activation
 Interaction with immune sensitized T-cells
 Direct interaction with
 Fibronectin
 Bacterial products
 Mediated through receptors
 FcγR
 C3bR
 Mannose
 CD14 LPS binds to soluble LPS binding
protein that is taken up
 Toll-like receptor

8. Features of activated macrophage
 Morphological
 Increase in size, adhesion, cytoplasmic granules,no.
of mitochondria
 Biochemical
 Increase in metabolic activity,enzymes, c-GMP,
Ca2+,prostaglandins, interferon
 Functional
 Increase in phagocytic activity
 Increase in microbicidal activity

11. Role of Macrophage in health
 Phagocytosis
 Microbicidal action
 Secretion of cytokines
 Antigen presentation
 Wound healing and removal of debris
 Destruction of senescent RBC’s in spleen

13. Phagocytosis

14. Microbicidal action
 Phagocytosis stimulates burst in oxygen
consumption ,glycogenolysis,glucose
oxidation production of ROI
 Oxygen dependent mechanism
 Oxygen independent mechanism

15. Products of Activated Macrophages

16. Cytokines

19. Healing
 Macrophages phagocytose foreign particles and
bacteria
 Macrophages bind to specific proteins of the
extracellular matrix
 Activated macrophages release
 platelet-derived growth factor
 Chemoattractant
 Mitogen for fibroblasts
 vascular endothelial growth factor
 Formation of granulation tissue.

20. Healing

21. Healing

22. Other functions
 Removal of
 Senescent RBC’s
 Obsolescent hematopoietic cells
 Coagulation products
 Antigen-antibody complexes
 Hematopoiesis
 GM-CSF secretion
 Tissue remodelling
 Blood coagulation
 t-PA, PAI, PG,TX A2, PAF

23. Macrophage in disease
 Chronic infections
 Atherosclerosis
 Malignancies
 Chronic inflammatory diseases

24. Chronic infections
 Remaining inaccessible to host immune system
 Microbes can interfere with receptor-mediated recognition,
phagocytosis and trafficking of bacteria to the degradative lysosome
 Bacteria that enter macrophages can avoid destructionby perturbing
the signalling that is required for the production of reactive oxygen
intermediates(ROI), reactive nitrogen intermediates (RNI) and
acidification (H+).
 By interfering with antigen processing or presentation, pathogens
can prevent macrophages from alerting other cells of immune
system to the identify the infectious agent
 Altered secretion of soluble cytokines.

25. Combating intracellular pathogens
 Bacterial pathogens presented to T cells
 Differentiation into TH1 cells release of IFN- γ
 IFN- γ activation of macrophages
 Phagocytosis by activated macrophages
 Release of IL-12 Further development of TH1
 Enhanced host response
 Recruitment of more inflammatory cells
 Granuloma

27. TB Granuloma
1:Central Caseation
2:epithelioid cells
and lymphocytes
3:Langhan’s Giant
Cell

28. Atherosclerosis : Fatty-Streak

29. Atherosclerosis : Advanced Lesion

30. Role in malignancies
 Tumor-associated Macrophages (TAMs) influence
tumor growth by modulation of the host immune system
 TAMs can
 mediate direct anti-tumor cytotoxicity
 produce cytotoxic molecules (H2O2, IL-1, TNF-α, NO, ROI)
 present TAAs
 produce immunostimulatory cytokines (IL-12)
 TAMs produce growth factors that
 promote cancer cell proliferation and dissemination
 enhance angiogenesis, and
 suppress lymphocyte responsiveness IL-10 and PGE2

31. Chronic inflammatory diseases
 Multiple sclerosis and RA
 Macrophages produce
 pro-inflammatory cytokines TNF- α, IL-1, and IL-6,
 chemoattractant cytokines IL-8 and MIP-1
 pro-inflammatory products of arachidonic acid metabolism
 toxic reactive oxygen and nitrogen intermediates
 tissue restructuring metalloproteinases
 Macrophages also secrete IL-10 and TGF-β
 inhibit the production of IL-1 and TNF-alpha and
 reduce generation of ROIs and RNIs

32. Diseases of Monocytes & Macrophages
 Monocytopenia
 Aplastic anemia
 Hairy cell leukemia
 Steroid therapy
 Monocytosis
 Benign(reactive)
 Clonal
 AMoL
 CMML
 CMoL
 Macrophage deficiency
 Osteopetrosis
 Inflammatory histiocytosis
 Storage Histiocytosis
 Neoplastic Histiocytosis
 Monocyte and Macrophage
Dysfunction
 a1-antitrypsin deficiency
 Chediak-Higashi Syndrome
 Chronic granulomatous
disease
 Steroid therapy
 Malakoplakia
 Smoking
 Whipple’s disease

33. Diseases of macrophages
 Reactive proliferation
 Storage disorders
 Hemophagocytic histiocytosis
 Familial
 Infectious
 Tumour associated
 Drug associated
 Sinus Histiocytosis
 Sinus Histiocytosis with Massive Lymphadenopathy
 Clonal proliferation
 Malignant Histiocytosis(Histiocytic sarcoma)
 Leukemias
 Acute Monocytic Leukemia
 Chronic Myelomonocytic Leukemia
 Langerhans’ Cell Histiocytosis

34. Lysosomal Storage diseases
Spingolipidoses
Gaucher's disease:-Deficient glucocerebrosidase enzyme
( AR) :- glucocerebroside accumulation
 Type I: most common,variable age group
:chronic course ,No CNS involvement
 Type II: Infantile form ,fatal in 1st yr of life
: acute neuronopathic form
 Type III: childhood
: slowly progressive neurodegenerative +
systemic involvement
Mostly in Jews of east Europe

35. Gaucher's disease
 Clinical feature :- mental retardation in infantile form,
HS megaly, cytopenia, erosive bone changes,
Hypersplenism pancytopenia thrombocytopenia
bleeding tendency
Bony changes : in type I & III
dimineralisation, failure of bone remodelling, cortical
thinning, osteonecrosis, Erlenmayor flask deformity of
femur
 Microscopy :- characteristics Gaucher cell
 Source of glucocerebroside
 Diagnosis

36. Gaucher cell
cell

37. Niemann-Pick disease
 Enzyme def. – sphingomyelinase
 Charac. by HS megaly & MR
 Type I:- complete def.
: severe infantile form
: extensive CNS + visceral involvement
: death in 3 years
 Type II: mild def.
: organomegaly + no CNS involvement
 Clinical feature:- infant, failure to thrive , abd.
Enlargement,may be LN pathy, rash & bony lesions
 Diagnosis
 Microscopy : Niemann Pick Cell ( sea blue histiocyte)

38. Niemann Pick Cell

39. Sinus Histiocytosis
 Non specific reactive
change
 Nodes draining sites of
inflammation and
malignancies
 Dilated sinuses filled with
histiocytes
 Often associated with
follicular or inter-follicular
hyperplasia
 In cancer thought to
represent host immune
response to tumor/ its
products

40. Haemophagocytic Syndrome
( Haemophagocytic lymphohistiocytosis)HLH
 Familial(?Autosomal recessive) or sporadic
 First two years of life
 Fever,hepatosplenomegaly,pancytopenia,jaundice
 CNS involvement common
 Macrophages engorged with phagocytosed blood cells
 CSF : increased mononuclear cells
 Rapidly fatal if untreated
 Chemotherapy/Stem cell transplantation
 Infection/disease/drug associated
 Viral,bacterial,fungal,protozoal:-self limited
 Precipitant -Malignancies,immune supression,auto-immune
diseases
 Phenytoin

41. Hemophagocytic Syndrome
Macrophage with ingested
normoblasts
Bone marrow aspirate showing
phagocytosis of neutrophil,
nucleated erythrocyte, and platelets
by benign histiocytes

42. Hemophagocytic Syndrome:Diagnosis
 Clinical
 Fever >=7 days with peaks >= 38.5˚C
 Splenomegaly>=3 cm
 Cytopenia affecting >=2 lineages in peripheral blood and
not caused by a hypocellular or dysplastic bone marrow
 Hypertriglyceridemia and/or hypofibrinogenimia
 Hemophagocytosis in bone marrow or spleen or
lymph nodes; no evidence of malignancy

43. Benign proliferative macrophage diseases
 Disorders with the common feature of skin nodules(0.5
to l cm)with macrophage infiltration
 Include
 Juvenile xanthogranuloma
 Xanthoma disseminata
 Multicentric reticulohistiocytosis
 Juvenile xanthogranuloma
 Touton cells are characteristic
 Phagocytosis is not prominent
 Self-limited to aggressive disease
 Usually appear in infancy,may be delayed until adult life.
 Usually involute spontaneously

44. Sinus Histiocytosis with Massive
Lymphadenopathy
 Rosai Dorfman Disease
 First two decades of life
 M:F 3:2 , Etiology unknown ?EBV or HSV-6
 Coexisting immune impairment
 Painless massive bilateral cervical LN
enlargement,fever,leucocytosis,raised ESR
 25 %-extra nodal – skin,orbit,nasopharynx,salivary
gland,bone,CNS etc
 Polyclonal proliferation of histiocytes
 Lymphophagocytosis and erythrophagocytosis
characteristic
 Phagocytosed cells remain viable: emperipolesis
 Usually self limited-recedes after 9-18 months of onset

45. Sinus Histiocytosis with Massive
Lymphadenopathy
distention of sinuses with
pale-staining histiocytes
macrophages with numerous
lymphocytes within

46. Malignant Histiocytosis
 Progressive, systemic proliferation of
neoplastic histiocytes
 Age-variable ,adults common
 Site- 1/3 LN, 1/3- skin,1/3-extranodal
 Presents with fever, night sweats,
weight loss, jaundice
 Lymphadenopathy with
hepatosplenomegaly and skin
infiltration,bony lytic lesion
 Large immature cells round to oval
,abundant cytoplasm with pleomorphic
nuclei and prominent nucleoli,clumped
chromatin,thick nuclear membrane
 Markers – CD68,lysozyme,CD 11c
CD45,HLA-DR
 Production of reticulin
 Highly aggressive

47. Acute Myelomonocytic Leukemia
 15-25% of AML cases
 Presents with
 Markedly elevated WBC
count
 Organomegaly
 Lymphadenopathy and other
tissue infiltration (monocytes
infiltrate)

48. Acute Monocytic leukemia
 10-12% of AML cases
 Older patients
 Often presents with extramedullary tissue infiltration
or mass
 Diagnostic Criteria : 80% or more nonerythroid bone
marrow cells are of monocyte lineage
 M5a (poorly differentiated); 80% or more monocyte lineage
cells are monoblasts
 M5b (differentiated); mature monocytes predominate in
peripheral blood (<80% of monocyte lineage cells are
monoblasts, usually <20%)

49. Acute Monocytic leukemia
 M5a:Monoblasts
 large with round nuclei,
 prominent nucleoli,lacy
chromatin
 moderate cytoplasm, variably
basophilic and delicate
azurophilic granules; no Auer
rods
 M5b:Mature monocyte
lineage cells
 folded or cerebriform nuclei
 less basophilic cytoplasm,
 more azurophilic granules

50. Chronic myelomonocytic leukemia
(CMML)
 Variable clinical presentation
 blood cytopenia
 increased blasts
 monocytosis of 1000 per mm3 or more
 less than 20% blasts and promonocytes
–marked leukocytosis with
monocytosis
–organomegaly
–minimal increase in blasts
–previously called Ph
chromosome negative CML

51. CMML
peripheral blood
monocytes in CMML
having basophilic
cytoplasm
hyperlobated nuclei,
abnormal granules

52. Langerhans Cell Histiocytosis
 Neoplastic disorder
 Includes
 Letterer-Siwe disease
 Hand-Schuller-Christian disease
 Eosinophilic granulomas
 Hashimoto-Pritzker disease
 Etiology unknown ?viral infection/cytokine imbalance
 Affects bones and soft tissues
 Presentation varies with age at onset
 Diabetes insipidus in up to 25% cases
 Characterized by presence of pathologic Langerhans
cells
 EM :Birbeck granules
 Express HLA-DR,S100,CD1a

53.  Eosinophilic granuloma:- solitary lesion charac by diffuse
infiltrate of benign histiocytes,lymphocytes,eosinophils
 All age group ,more common Ist decade
 Skull,femur,ribs,vertebrae,pelvis
 Lytic lesions
 Hand Schuller Christian disease:-
 Polyostotic eosinophilic granuloma
 Multiple bony lesions+ focal visceral infiltrates in liver, spleen,lung
 Older children
 Triad- lytic bone lesion+ exophthalmous + Diabetes insipidus
 Letterer Siwe disease:- < 3 yrs
 Acute & progressive
 Systemic disease from onset – infiltrate in bone, liver,LN, lung, skin

54. Langerhans Cell Histiocytosis
Birbeck granules
Langerhans’ Cells