Histology, Monocytes (2024)

Introduction

Monocytes are white blood cells that derive from the bone marrow. A monocyteis part of the innate immune response andfunctions to regulate cellular homeostasis, especially in the setting of infection and inflammation.[1]They account for approximately 5% of circulating nucleated cells in normal adult blood.[2] The half-life of circulating monocytes is approximately one to three days.[3]Monocytopenia, a decrease in circulating monocytes, is a common finding in myelodysplastic syndromes.[4]While monocytosis, an increase in circulating monocytes, is a common finding in the peripheral blood, especially in association with infection, trauma, medications, autoimmune disease, and some malignancies.[1]When monocytosis is persistent and unexplained, the diagnosis of chronic myelomonocytic leukemia merits investigation.[5]

Issues of Concern

When there is a suspected myeloid neoplasm with monocytic differentiation, it is challenging and essential to accurately classify monocytes as mature or immature. There is no definitive test to identify immature monocytes. Flow cytometry identifies molecules on the surface of such cells, known as cluster of differentiation (CD) markers. Such markers canprovide information to help in estimating the approximate populations of mature and immature monocytes.[6]Along with flow cytometry, the cell’s morphology requires assessment due to the atypical expression of CD markers during neoplastic growth.[5]In chronic myelomonocytic leukemia, there is persistent peripheral blood monocytosis with approximately double the amount of normally circulating monocytes.[5]The bone marrow must have less than 20% blasts (immature cells) present for the clinician to render a diagnosis of chronic myelomonocytic leukemia.[7]

Structure

Monocytes are the largest white blood cell, measuring between 12 to 20 µm in diameter, approximately twice the size of red blood cells.[2] Monocytes are typically easy to identify in the peripheral blood by their relatively large size and convoluted bilobed nuclei, often described as kidney-shaped.[8]

Function

Monocytes are a crucial component of the innate immune system.[9] A monocyte is a type of white blood cell that differentiates into populations of macrophages and dendritic cells to regulate cellular homeostasis, especially in the setting of infection and inflammation.[1]Monocytes have two distinct roles; they regularly patrol the body for microbial cells and orchestrate an immune response in times of infection and inflammation.[1]Monocytes have toll-like receptors on their surfaces that interact with PAMPS (pathogen-associated molecular patterns) found on invading microbial cells.[10]In response to such stimuli, monocytes migrate from the bone marrow into the blood circulation and infiltrate tissues within12 to 24 hours.[11]

To infiltrate the affected sites, the monocytes must first secure themselves to the endothelium and then loosely roll along the vascular surface. The monocyte then firmly adheres to the endothelium and finally passes through the endothelial cells through a process known as diapedesis. Monocytes are then able to penetrate the endothelial basem*nt membrane and migrate to the area of inflammation.[12]This process occurs through the interaction of molecules on both the monocyte and the endothelial cell surfaces.[13] Growth factors and cytokines determine the monocyte subtype.[14]Monocytes function as phagocytes and antigen-presenting cells in the peripheral blood to ingest and remove microorganisms, foreign material, and dead or damaged cells.[1]Antigen-presenting cells include macrophages, dendritic cells, B lymphocytes, and activated endothelial cells.[15]

Macrophages can further differentiate into specialized macrophages based on their location.[16] These include histiocytes in the connective tissue, microglia cells in the brain, osteoclast in the bone, mesangial cells in the kidney, and alveolar macrophages in the lungs.[17] Monocytes can produce cytokines that recruit additional cells and proteins to the affected area mounting a substantial immune response.[1]The types of cytokines released will vary depending on the function.[18]To restore homeostasis, monocytes can contribute to remodeling and healing via anti-inflammatory cytokines.[18]

Tissue Preparation

The histological characterizing of monocytes occurs in three main steps. These steps include obtaining and preparing asample of wholeblood, flow cytometry, and monocyte gating. The process of preparing the whole bloodis a multistep chemical procedure that involves lysing the cells, marking the cells, and ultimately obtaining a concentrated sample for use in the study. Flow cytometry of the sample then allows for the characterizing of the monocytes depending on the markers they process. Monocyte gating is a visualmeans by whichto organize the collected data to show the percentage of each monocyte subset.[19]

Histochemistry and Cytochemistry

The cluster of differentiation (CD) markers are specific molecules found onthe surface of a cell that differentiates cells from one another, as well as from surrounding tissue. The CD markers are specific to the subtype of monocyte and the type of response mounted by the immune system.[6]Common CD markers include CD4, CD11b, CD14, CD16, and CD33.[20]

Microscopy, Light

The single bi-lobed nucleus has mature chromatin, and the cytoplasm is moderate to abundant and frequently shows irregular basophilic edges. Upon staining with non-specific esterases, the nucleus is pale violet, while the abundant cytoplasm stains pale grey to blue with numerous reddish-blue cytoplasmic granules.[2]

Microscopy, Electron

On electron microscopy, monocytes appear to have a single nucleus and abundant cytoplasm with scattered granules as well as organelles. Such organelles include numerous mitochondria, a Golgi apparatus, microvesicles, microtubules, and microfilaments.[21]

Pathophysiology

The role of monocytes is versatile and related to various types of disorders and infectious processes, and inflammation. Monocytosis and monocytopenia have been identifying factors in multiple hematologic disorders, such as leukemias and myelodysplastic syndromes.[22]Monocytosis is present in numerous inflammatory and immune disorders, such as connective tissue diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and sarcoidosis.[23][24][25]Monocytes play a crucial role in the immune response to acute infectious and inflammatory processes, such as mycobacterial infections and varicella-zoster virus.[26][27]Monocytosis also occurs in myocardial infarction and is often related to the serum creatinine kinase and extent of infarction.[28]Monocytes can remove the debris and help with remodeling following myocardial infarctions.[29]

Clinical Significance

Monocytes are acritical component of the innate immune system. Theyare the source of many other vital elements of the immune system, such as macrophages and dendritic cells. Monocytesplay a role in both the inflammatory and anti-inflammatoryprocessesthat take place during an immune response. Monocytes, and their abundanceor lack thereof, can provide significant identifying cluesfor the diagnosis ofseveral hematologic disorders and inflammatory and immune disorders.

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References

1.

Yáñez A, Coetzee SG, Olsson A, Muench DE, Berman BP, Hazelett DJ, Salomonis N, Grimes HL, Goodridge HS. Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes. Immunity. 2017 Nov 21;47(5):890-902.e4. [PMC free article: PMC5726802] [PubMed: 29166589]

2.

Prinyakupt J, Pluempitiwiriyawej C. Segmentation of white blood cells and comparison of cell morphology by linear and naïve Bayes classifiers. Biomed Eng Online. 2015 Jun 30;14:63. [PMC free article: PMC4485641] [PubMed: 26123131]

3.

Patel AA, Zhang Y, Fullerton JN, Boelen L, Rongvaux A, Maini AA, Bigley V, Flavell RA, Gilroy DW, Asquith B, Macallan D, Yona S. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med. 2017 Jul 03;214(7):1913-1923. [PMC free article: PMC5502436] [PubMed: 28606987]

4.

Saeed L, Patnaik MM, Begna KH, Al-Kali A, Litzow MR, Hanson CA, Ketterling RP, Porrata LF, Pardanani A, Gangat N, Tefferi A. Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients. Blood Cancer J. 2017 Mar 31;7(3):e550. [PMC free article: PMC5380913] [PubMed: 28362440]

5.

Itzykson R, Fenaux P, Bowen D, Cross NCP, Cortes J, De Witte T, Germing U, Onida F, Padron E, Platzbecker U, Santini V, Sanz GF, Solary E, Van de Loosdrecht A, Malcovati L. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet. Hemasphere. 2018 Dec;2(6):e150. [PMC free article: PMC6745959] [PubMed: 31723789]

6.

Hamers AAJ, Dinh HQ, Thomas GD, Marcovecchio P, Blatchley A, Nakao CS, Kim C, McSkimming C, Taylor AM, Nguyen AT, McNamara CA, Hedrick CC. Human Monocyte Heterogeneity as Revealed by High-Dimensional Mass Cytometry. Arterioscler Thromb Vasc Biol. 2019 Jan;39(1):25-36. [PMC free article: PMC6697379] [PubMed: 30580568]

7.

Tcyganov E, Mastio J, Chen E, Gabrilovich DI. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol. 2018 Apr;51:76-82. [PMC free article: PMC5943174] [PubMed: 29547768]

8.

Skinner BM, Johnson EE. Nuclear morphologies: their diversity and functional relevance. Chromosoma. 2017 Mar;126(2):195-212. [PMC free article: PMC5371643] [PubMed: 27631793]

9.

Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol. 2009;27:669-92. [PubMed: 19132917]

10.

Santoni G, Cardinali C, Morelli MB, Santoni M, Nabissi M, Amantini C. Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons. J Neuroinflammation. 2015 Feb 03;12:21. [PMC free article: PMC4322456] [PubMed: 25644504]

11.

Issekutz AC, Issekutz TB. Quantitation and kinetics of blood monocyte migration to acute inflammatory reactions, and IL-1 alpha, tumor necrosis factor-alpha, and IFN-gamma. J Immunol. 1993 Aug 15;151(4):2105-15. [PubMed: 8345197]

12.

Maslin CL, Kedzierska K, Webster NL, Muller WA, Crowe SM. Transendothelial migration of monocytes: the underlying molecular mechanisms and consequences of HIV-1 infection. Curr HIV Res. 2005 Oct;3(4):303-17. [PubMed: 16250878]

13.

Henderson RB, Hobbs JA, Mathies M, Hogg N. Rapid recruitment of inflammatory monocytes is independent of neutrophil migration. Blood. 2003 Jul 01;102(1):328-35. [PubMed: 12623845]

14.

Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, Chalasani G, Taboas JM, Lakkis FG, Metes DM. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One. 2017;12(4):e0176460. [PMC free article: PMC5406034] [PubMed: 28445506]

15.

Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol. 2017 Jun;17(6):349-362. [PubMed: 28436425]

16.

Varol C, Yona S, Jung S. Origins and tissue-context-dependent fates of blood monocytes. Immunol Cell Biol. 2009 Jan;87(1):30-8. [PubMed: 19048016]

17.

Schultze JL. Chromatin Remodeling in Monocyte and Macrophage Activation. Adv Protein Chem Struct Biol. 2017;106:1-15. [PubMed: 28057208]

18.

Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res. 2014 Jan 07;2(1):1. [PMC free article: PMC3892095] [PubMed: 24398220]

19.

Marimuthu R, Francis H, Dervish S, Li SCH, Medbury H, Williams H. Characterization of Human Monocyte Subsets by Whole Blood Flow Cytometry Analysis. J Vis Exp. 2018 Oct 17;(140) [PMC free article: PMC6235554] [PubMed: 30394370]

20.

Stansfield BK, Ingram DA. Clinical significance of monocyte heterogeneity. Clin Transl Med. 2015;4:5. [PMC free article: PMC4384980] [PubMed: 25852821]

21.

Puhm F, Afonyushkin T, Resch U, Obermayer G, Rohde M, Penz T, Schuster M, Wagner G, Rendeiro AF, Melki I, Kaun C, Wojta J, Bock C, Jilma B, Mackman N, Boilard E, Binder CJ. Mitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells. Circ Res. 2019 Jun 21;125(1):43-52. [PubMed: 31219742]

22.

Olingy CE, Dinh HQ, Hedrick CC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol. 2019 Aug;106(2):309-322. [PMC free article: PMC6658332] [PubMed: 30776148]

23.

Roberts CA, Dickinson AK, Taams LS. The Interplay Between Monocytes/Macrophages and CD4(+) T Cell Subsets in Rheumatoid Arthritis. Front Immunol. 2015;6:571. [PMC free article: PMC4652039] [PubMed: 26635790]

24.

Burbano C, Villar-Vesga J, Orejuela J, Muñoz C, Vanegas A, Vásquez G, Rojas M, Castaño D. Potential Involvement of Platelet-Derived Microparticles and Microparticles Forming Immune Complexes during Monocyte Activation in Patients with Systemic Lupus Erythematosus. Front Immunol. 2018;9:322. [PMC free article: PMC5837989] [PubMed: 29545790]

25.

Fraser SD, Sadofsky LR, Kaye PM, Hart SP. Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis. Sci Rep. 2016 Dec 08;6:38689. [PMC free article: PMC5144133] [PubMed: 27929051]

26.

Delcroix M, Heydari K, Dodge R, Riley LW. Flow-cytometric analysis of human monocyte subsets targeted by Mycobacterium bovis BCG before granuloma formation. Pathog Dis. 2018 Nov 01;76(8) [PMC free article: PMC6276273] [PubMed: 30445573]

27.

Kennedy JJ, Steain M, Slobedman B, Abendroth A. Infection and Functional Modulation of Human Monocytes and Macrophages by Varicella-Zoster Virus. J Virol. 2019 Feb 01;93(3) [PMC free article: PMC6340020] [PubMed: 30404793]

28.

Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010 Jun 08;121(22):2437-45. [PMC free article: PMC2892474] [PubMed: 20530020]

29.

Dutta P, Nahrendorf M. Monocytes in myocardial infarction. Arterioscler Thromb Vasc Biol. 2015 May;35(5):1066-70. [PMC free article: PMC4409536] [PubMed: 25792449]

Disclosure: Valerie Espinoza declares no relevant financial relationships with ineligible companies.

Disclosure: Prabhu Emmady declares no relevant financial relationships with ineligible companies.