Reactive lymphocyte

{{Short description|Lymphocytes that become large as a result of antigen stimulation}} thumb|200px|Reactive lymphocyte surrounded by red blood cells

In immunology, '''reactive lymphocytes''', '''variant lymphocytes''', '''atypical lymphocytes''', '''Downey cells''' or '''Türk cells''' are cytotoxic (CD8<sup>+</sup>) lymphocytes that become large as a result of antigen stimulation. Typically, they can be more than 30 μm in diameter with varying size and shape.

== Discovery == Reactive lymphocytes were originally described by W. Türk in 1907 in the peripheral blood of patients with infectious mononucleosis. Later in 1923 the features of the reactive lymphocytes were characterized in greater detail by Hal Downey and C.A. McKinlay, who also discovered the association with EBV and CMV.<ref name="pmid8190136">{{cite journal |last1=Cabot |first1=Richard C. |last2=Scully |first2=Robert E. |last3=Mark |first3=Eugene J. |last4=McNeely |first4=William F. |last5=McNeely |first5=Betty U. |last6=Rosenfield |first6=Cathy G. |last7=Kaplan |first7=Mark A. |date=June 1994 |title=Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 24-1994. A two-year-old boy with thrombocytopenia, leukocytosis, and hepatosplenomegaly |journal=N. Engl. J. Med. |volume=330 |issue=24 |pages=1739–46 |doi=10.1056/NEJM199406163302408 |pmid=8190136}}</ref><ref>{{cite journal | last1=Downey | first1=Hal|last2=McKinlay|first2=C.A.| title=Acute Lymphadenosis Compared with Acute Lymphatic Leukemia| journal=Archives of Internal Medicine| volume=32 | issue=1 | date=1 July 1923 | issn=0003-9926 | doi=10.1001/archinte.1923.00110190085006 | pages=82–112}}</ref>

== Morphology == Downey and McKinlay first described the atypical lymphocytes seen in cases of infectious mononucleosis. They further categorized the atypical lymphocytes of different etiologies under three subtypes:<ref>{{cite journal |last1=Downey |first1=Hal |title=Acute Lymphadenosis Compared with Acute Lymphatic Leukemia |journal=Archives of Internal Medicine |date=July 1923 |volume=32 |issue=1 |pages=82 |doi=10.1001/archinte.1923.00110190085006 }}</ref>

# Type I as highly differentiated "leukocytoid lymphocyte", round-to-lobulated nucleus, mature clumped chromatin with or without nucleoli and with varying degree of basophilia in the cytoplasm. # Type II as larger cells with round-to-lobulated nucleus, chromatin resembling that of plasma cells, moderate amount of cytoplasm with mild basophilia. # Type III cells are large cells with a round to slightly indented nucleus, chromatin mostly immature with diffuse sieve-like arrangements and nucleoli.

Downey type II cell is the most common type of reactive lymphocyte. In general, those cells may vary in morphologic detail as well as surface marker characteristics since this is the result of a polyclonal immune response to antigenic stimulation. All three types of Downey cells were observed along with some other variants such as larger cells with deeply convoluted nucleus, cells with crystalline rods and granules in the cytoplasm, flame cells, Mott cells, and some intermediate forms.<ref>{{cite journal |last1=Acharya |first1=Shreyam |last2=Ningombam |first2=Aparna |last3=Sarkar |first3=Abhirup |last4=Kumar |first4=Kundan |title=Diverse Atypical Lymphocytes in the Peripheral Blood Smear of Dengue Patients: Crystalline Rods, Mott Cells, and Downey Cells |journal=Journal of Applied Hematology |date=July 2022 |volume=13 |issue=3 |pages=163–165 |doi=10.4103/joah.joah_33_21 |doi-access=free }}</ref> Flame cells are plasma cells characterized by a pink fringe of cytoplasm, often observed in the bone marrow of cats, especially in conditions such as multiple myeloma and chronic infections.<ref>{{cite book |last1=Haddad |first1=Jamie L. |last2=Roode |first2=Sarah C. |last3=Grindem |first3=Carol B. |title=Cowell and Tyler's Diagnostic Cytology and Hematology of the Dog and Cat |chapter=Bone Marrow |date=2020 |pages=468–506 |doi=10.1016/B978-0-323-53314-0.00027-4 |isbn=978-0-323-53314-0 }}</ref>

The common features of reactive lymphocytes:<ref name=":0">{{cite journal |last1=Kalele |first1=Ketki P |title=Atypical Lymphocytes and Cellular Cannibalism: A Phenomenon, First of its Kind to be Discovered in Chronic Periapical Lesions |journal=Journal of Clinical and Diagnostic Research |date=2016 |volume=10 |issue=4 |pages=ZC01-4 |doi=10.7860/JCDR/2016/16902.7519 |pmc=4866235 |pmid=27190937 }}</ref>

* larger than normal size, sometimes with a diameter of more than 30 microns;

* nucleus can be round, elliptic, indented, cleft, or folded; * the cytoplasm is often abundant and can be basophilic – most often, the cytoplasm is gray, pale blue, or deep blue in color; * vacuoles and/or azurophilic granules are also sometimes present; * histochemistry shows increased concentrations of acid phosphatase, phosphorylase, and non-specific esterase; * prominent clusters and rosettes of free ribosome; * presence of small vacuoles near the edge of the cytoplasm as well as invaginations in the cell surface.

=== Molecular markers === Atypical lymphocyte population often express features of activated CD8+ T cells, such as CD29, CD38, HLA-DR, CD45RO and CD95. Expression of CD25 was on the other hand decreased.<ref name=":2">{{cite journal |last1=Hudnall |first1=S. David |last2=Patel |first2=Jyoti |last3=Schwab |first3=Hanna |last4=Martinez |first4=José |title=Comparative immunophenotypic features of EBV-positive and EBV-negative atypical lymphocytosis |journal=Cytometry Part B |date=September 2003 |volume=55B |issue=1 |pages=22–28 |doi=10.1002/cyto.b.10043 |pmid=12949956 }}</ref>

Expressed molecular markers may vary depending on many factors. For example, CD57 expression seems to be significantly decreased only in patients with EBV infections.<ref name=":2" />

== Function == The atypical lymphocytes have been best studied from blood of patients with infectious mononucleosis. Early studies suspect that atypical lymphocytes could have both T or B cells features; now it is more suggested that reactive lymphocytes are activated T-lymphocytes produced in response to infected B-lymphocytes.<ref name=":1">{{cite journal |last1=Shiftan |first1=Thomas A. |last2=Mendelsohn |first2=John |title=The circulating 'atypical' lymphocyte |journal=Human Pathology |date=January 1978 |volume=9 |issue=1 |pages=51–61 |doi=10.1016/S0046-8177(78)80007-0 |pmid=631844 }}</ref><ref name=":0" />

Reactive lymphocytes have been found to accumulate in areas of inflammation like the liver and pharynx of individuals with infectious mononucleosis and skin window preparations. In infectious mononucleosis, the atypical lymphocytes are one component of a normal immune system that helps to control potentially fatal Epstein-Barr virus-induced B-cell lymphoma in human.

==Causes== Reactive lymphocytes are usually associated with viral illnesses, but they can also be present as a result of drug reactions (such as phenytoin), immunizations, radiation, and hormonal causes (such as stress and Addison's disease), as well as some autoimmune disorders (such as rheumatoid arthritis).<ref name=":1" />

Some pathogen-related causes include:<ref name=":2" /> * Epstein–Barr virus * Cytomegalovirus * ''Toxoplasma gondii'' * ''Treponema pallidum'' (syphilis) * ''Streptococcus agalactiae'' (group B streptococci) * Hepatitis C * Hantavirus<ref>{{cite journal |vauthors=Peters CJ, Khan AS | title=Hantavirus pulmonary syndrome: the new American hemorrhagic fever | journal=Clin Infect Dis | year=2002 | volume=34 | pages=1224–31 | pmid=11941549 | doi=10.1086/339864 | issue=9 | doi-access=free }}</ref>

=== Association with COVID-19 === The presence of Downey cells were observed in many COVID-19 cases, together with the atypical plasmacytoid lymphocytes (which could be one of the less usual atypical lymphocyte types).<ref>{{Cite journal |last1=Chong |first1=Vanessa C. L. |last2=Lim |first2=Kian Guan Eric |last3=Fan |first3=Bingwen Eugene |last4=Chan |first4=Stephrene S. W. |last5=Ong |first5=Kiat H. |last6=Kuperan |first6=Ponnudurai |date=5 May 2020 |title=Reactive lymphocytes in patients with COVID-19 |journal=British Journal of Haematology |language=en |volume=189 |issue=5 |page=844 |doi=10.1111/bjh.16690 |issn=0007-1048 |pmc=7262365 |pmid=32297330}}</ref><ref>{{Cite journal |last1=El Jamal |first1=Siraj M. |last2=Salib |first2=Christian |last3=Stock |first3=Aryeh |last4=Uriarte-Haparnas |first4=Norlita I. |last5=Glicksberg |first5=Benjamin S. |last6=Teruya-Feldstein |first6=Julie |last7=Dembitzer |first7=Francine R. |last8=Nadkarni |first8=Girish N. |last9=Firpo-Betancourt |first9=Adolfo |date=10 June 2020 |title=Atypical lymphocyte morphology in SARS-CoV-2 infection |journal=Pathology - Research and Practice |language=en |volume=216 |issue=9 |article-number=153063 |doi=10.1016/j.prp.2020.153063 |pmc=7284261 |pmid=32825937}}</ref>

Some observations even suggest that the presence of particular reactive lymphocytes in some of the infected patients could be an indicator of a better prognosis of the disease.<ref>{{Cite journal |last1=Rodellar |first1=José |last2=Barrera |first2=Kevin |last3=Alférez |first3=Santiago |last4=Boldú |first4=Laura |last5=Laguna |first5=Javier |last6=Molina |first6=Angel |last7=Merino |first7=Anna |date=2022-05-23 |title=A Deep Learning Approach for the Morphological Recognition of Reactive Lymphocytes in Patients with COVID-19 Infection |journal=Bioengineering |language=en |volume=9 |issue=5 |page=229 |doi=10.3390/bioengineering9050229 |pmid=35621507 |pmc=9137554 |issn=2306-5354|doi-access=free }}</ref>

== See also ==

* T cell * Infectious mononucleosis

==References== <references />

== External links == * [http://www.int-pediatrics.org/PDF/Volume_18/18_1/20_22ip1803_WEB.pdf Review Article: The Atypical Lymphocyte] – International Pediatrics Volume 18, No. 1; Michael W. Simon. * [https://web.archive.org/web/20070929044457/http://www.api-pt.com/pdfs/2002Bheme.pdf Educational Commentary: Blood Cell Identification] – American Society for Clinical Pathology article.

Category:Lymphocytes Category:Abnormal clinical and laboratory findings for blood Category:Hematopathology