The plasma cells of the cerebrospinal fluid

227

Journal of the neurological Sciences

Elsevier Publishing Company, Amsterdam - Printed in The Netherlands

The Plasma Cells of the Cerebrospinal Fluid A. Pl~TER Neurological Clinic, Medical University of Budapest (Director: Prof. B~la Hordnyi), Budapest (Hungary)

(Received 27 April, 1966)

INTRODUCTION The haematological and immunological literature dealing with the morphological peculiarities of plasma cells, with their r61e in the defensive mechanisms of the body and with the changes which occur in these cells in various diseases, is scanty. CAJAL (1890) mentioned as characteristic features of the plasma cells: oval shape, basophilic cytoplasm, clear perinuclear zone, nucleus displaced towards the periphery, with a wheel-spoke arrangement of the nuclear chromatin and with 1-2 nucleoli in the nucleus. On the basis of the immature forms which are seen, oiz. plasmoblasts, proplasmocytes and plasmocellular reticulum cells, it can be assumed that plasma cells are differentiated partly from undifferentiated reticulum cells and partly from lymphoidal reticulum cells during lymphogenesis. Accordingly two types of plasma-cells, namely the reticular and lymphoid forms can be distinguished (HEILMEYERAND BEGEMANN 1955; BERNARDAND GRANBOULAN1960; ROHR 1960; STOBBE 1960; THIERY 1960). Recent investigations have demonstrated the secretory activity of the plasma cells (MILLER 1931; HECKNER 1949; HORSTER1950; MOESCHLINet al. 1951; THIERY 1960) while experimental and clinical data have shown a direct connection between plasmacell proliferation and gamma globulin production (BING AND PLUM 1937; BJORNEBOE AND GORMSEN 1941; FAGRAEUS1948a and b; EHRICH 1955), indicating the decisive role of the plasma cells in antibody production. The leptomeningeal plasma cells differ morphologically from the haematogenic ones only in the lack of wheel-spoke arrangement of their nuclear chromatin. Many authors refer to immature forms of plasma cells being seen in the spinal fluid (CSF) (WEDEMEYER1935; FANCONI 1939; SCH()NENBERG1951, 1953, 1955). These, as well as the cells with large nuclei showing deeply staining plasma mentioned by SAYK AND SCHMIDT(1956), the basophil cells of BISCHOFE(1960, 1964), SAYK'S (1959, 1960) "lymphoid cells" and intermediate cell forms make it possible that the plasma cells of the CSF also pass through the developmental phases known to occur in haematology. The significance of plasma-cells in the defensive activity of the nervous system (CNS) is reflected by the fact that plasmocellular cytological reactions (Voss 1939; SAYK 1959, 1960; BISCHOFF1960, 1964; SCHMIDT1960, 1965) and a rise of gamma globulin in the J. neurol. Sci. (1967) 4:227-239

228

A. PETER

spinal fluid (MATIAR AND SCHMIDT 1957, 1958; CERVOS-NAVARROAND MA-flAR 1959: LOWENTHALet al. 1960) have been demonstrated in the same pathological processes (e.g. multiple sclerosis, neurosyphilis). Plasma cells cannot be detected in the CSF of healthy subjects. Their appearance may be observed mostly in acute and chronic inflammatory diseases of the CNS, particularly in viral infections (FANCONI 1939 ; SCHONENBERG195 l, 1953 ; SAYK 1959, 1960; OLISCHER 1964; BISSCHOFF 1960, 1964; SCHMIDT 1960, 1965). Many authors attach importance to the presence of plasma cells in differentiating between tuberculous and non-bacterial processes. They have been observed in allergic disorders of the CN S (QUADRA 1949; ESSELLIER AND FORSTER 1957; KNITTEL AND SCHMIDT 1958) associated with an eosinophJlia in the CSF, as well as in granulomatous processes involving the nervous system (SAYK 1959, 1960; BISCHOFF 1960, 1964). A marked plasmocellular reaction, however, is considered to be characteristic only of an acute exacerbation of multiple sclerosis or neurosyphilis (SAYK 1959, 1960; BISCHOEF1960, 1964; SCHMIDT1960, 1965). MATERIAL AND METHODS

In our clinic we have carried out investigations on 500 centrifuged deposits of the CSF from 300 patients according to SAYK'S (1959) method (stained with haematoxylineosin; methylgreen-pyronin; metyhlene blue; berlin blue), noting the morphological characteristics, the eytogenesis and function of the plasma cells. RESULTS

The common morphological features of haematogenic and leptomeningeal plasma cells, among them a considerable polymorphism was conspicious in our series. Polymorphism was determined by the appearance of the cell and nucleus, the situation of the latter, peculiarities of the perinuclear zone, the nuclear structure and the relation between nucleus and plasma. We noted rounded, oval or irregularly-shaped cells; cells with bean-shaped, oval and round nuclei; smaller or larger perinuelear zones; the nucleus plasma ratio shifted in favour of the nucleus; cells with cytoplasm stained more deeply; nuclei with dense or fine ehromatin structure (Figs. 1-4). On the basis of haematologieal observations it is known that the loose nuclear structure, the relatively large nucleus and marked basophilia of the cytoplasm are characteristic features of immature forms. Among variants of the plasma cells, we observed in many cases structures characteristic of undeveloped cells. On the basis of these observations it can be supposed that the observed polymorphism of plasma cells in the CSF reflects the different stages of their developmental cycle. Immature plasma cells with large nuclei and loose nuclear chromatin structure were found in the first place in cases in which intense plasmocellular invasion, mitoses (Fig. 5) and binuclear forms (Fig. 6) pointed to a severe state of irritability of the leptomeninges. In one patient with choriomeningitis whose CSF showed 38 70 of plasma cells and in the CSF of lour patient with cerebral cyzficercosis who showed 52 7ooof plasma cells, we observed in the fluid barely differentiated plasma cells and plasmoblasts (Fig. 7). In cases which showed a smaller percentage of J. neurol. Sei. (1967) 4:227-239

229

THE PLASMA CELLS OF THE CEREBROSPINAL FLUID SOME MORPHOLOGICAL VARIANTS OF THE PLASMA-CELLS OF THE C S F

Fig. 1. Plasma cell ill the CSF of a patient with cerebral cysticercosis.

Fig. 2. Plasma cell in acute meningitis.

Fig. 3. Plasma cell in pyocyaneus meningitis.

non-bact~iM

Fig. 4. Plasma cell in SSLE.

MITOSIS IN THE C S F

g~

9

Fig. 5. Mitosis in a plasma-cellular polyradiculitis. The type of the cell cannot be determined. J. neuroL Sci. (1967) 4:227-239

230

A. PI~TER IMMATURECELL FORMSIN "rUECSF

Fig. 6. Undifferentiated reticulum cell, binocular plasma cell with small vacuoles in the cytoplasm in choriomeningitis.

Fig. 8. Plasmo-cellular reticulum cell in the CSF of a patient with chronic nonbacterial meningitis (?sarcoidosis).

Fig. 7. Blast cell in cerebral cysticercosis.

Fig. 9. Lymphoidal reticutum cell in plasmo-celtular polyradiculitis.

Fig. I 0. Immature plasma cell in cerebral cysticerosis. J. neuroL Sci. (1967) 4:227-239

THE PLASMACELLSOF THE CEREBROSPINALFLUID

231

plasma ceils in the CSF we demonstrated more mature forms as a rule. Consequently the appearance of immature forms of plasma cells in the CSF of our patients was connected in the first place with the intensity of the plasmocytic reaction. During the qualitative analysis of immature cell forms in the CSF we found in some of our cases cells, which suggested either that leptomeningeal plasma cells may derive from undifferentiated reticulum cells or that they may come into being in the course of lymphogenesis through the 'blast' phase. The plasmocellular reticulum cell observed in the CSF of one of our patients with chronic meningitis of unknown aetiology (Fig. 8) as an intermediate form between the undifferentiated reticulum cell (Fig. 6) and the mature plasma cell, favours the reticular origin. However, the lymphoidal reticulum cell (Fig. 9) and plasmoblast (Fig. 10) found in association with cerebral cysticercosis, on the other hand, suggests that differentiation of plasma cells occurs during lymphogenesis. On the basis of plasma cell forms observed in the CSF of our patients it is concluded that the developmental stages of leptomeningeal plasma-cells can probably be regarded as similar to those of the haematogenic cells, according to the following pattern: iymphoblast --~ lymphocyte f

lymphoidal reticulum cell undifferentiated reticulum cell "x

plasmoblast --->lymphoidal plasma cell plasmocellular ~ reticular reticulum cell plasmacell

On the basis of phase-contrast microscopic examinations carried out on the plasma cells of patients with myeloma and on the increased numbers of plasma cells which appear during experimental immunisation, some authors (FAGRAEUS 1948a and b; KEUNING AND VAN DER SLIKKE 1950; MOESCHLINet al. 1951; WHITE 1954; THIERY 1960) have considered that the young forms of plasma cells are immunologically active. The question arises as to whether the undifferentiated plasma cells observed in the CSF can be considered as proof of the fact, that the leptomeningeal plasma cells play an active part in increasing the antibodies, that can often be isolated from the CSF. Observations made on the meningograms* of our patients partly support and partly refute this suggestion. MILLER (1931), FAGRAEUS (1948a and b), MOESCHLINet al. (1951), STOaBE (1960), THmRY (1960) and others considered the drop-like formations discernible in the plasma cells of the bone marrow and in the peripheral blood to be a morphological manifestation of their secretory activity. Many years ago ALZHEIMER (1897, 1907), ROTH (1915) and SPIELMEYER(1922), referred to cells containing Russell's bo&es in the central nervous system, fiist and foremost in patients with progressive paralysis. Similar cells in the CSF are mentioned by SCHrNENBERG(1951) in cases of non-bacterial meningitis, by OLISCHER(1964, 1966) in cases of viral infections of the CNS and also by SAYK(1959, 1960). SCHrNENBERG * The distribution of various cellforms found in the CSF is calledthe meningogramby FANCONI(1939).

J. neuroL ScL (1967) 4:227-239

232

A. PETER VACUOLES AND DROP-LIKE

FORMATIONS IN THE CYTOPLASM OF THE SPINAL FLUID PLASMA CELLS

Fig. 11. Plasma cells with vacuoles filled with eosinophilic masses in cerebral cysticercosis.

Fig. 12. Plasma cell with fine vacuole-like formations of different size in the cytoplasma of a patient with chronic non-bacterial meningitis.

~i¸ :i!!i il¸

Fig. 13. Plasma cell with bigger vacuole-like intraplasmatic formations in chronic non-bacterial meningitis.

Fig. 14. Drop-like appearances in the cytoplasm of a plasma cell in cerebral cysticercosis.

i i iii i IIii i iii iiiiiii i//iiiiii!ii!iiiii¸¸¸ii? Fig. 15. Changes resembling Russell's bodies in the plasma cell in cerebral cysticercosis. J. neurol. Sci. (1967)4:227-239

THE PLASMACELLSOF THE CEREBROSPINALFLUID

233

(1951, 1953, 1955) regards these alterations in the plasma cells as being the manifestation of a specific functional state. OLISCHER(1964, 1966) demonstrated drops in the plasma cells simultaneously with plasmoceUular reactions in the CSF and raises the question as to whether there exists any connection between these drops and the production of antibodies in the plasma cells in the CSF. In the CSF of our patient with cerebral cysticercosis, in addition to a gamma globulin which was 50.6 ~o of total protein and 52 ~o of plasma cells (among these a considerable number of immature forms), we found in the nucleus, on the border of the nucleus and plasma, and in the cytoplasm of the plasma cells vacuoles, filled up with eosinophilic masses (Fig. 11). In other cells from the same patient there were observed drop-like formations (Figs. 14 and 15). Fig. 15 shows a cell containing material resembling the Russell's bodies known in haematology. In the CSF of a case of non-bacterial meningitis in which 53.2 ~o of the total protein was gamma globulin, vacuoles of different sizes were seen within the plasma cells (Figs. 12 and 13). If we group the cells according to the size of the intraplasmatic droplets, it is our impression that we discern the successive phases of a functional state. The drops and vacuoles within the cytoplasm of the plasma cells can be regarded as specific degenerative phenomena. They may be considered as degenerative in the sense that the cell is incapable of excreting the material which is secreted; as a result of storing these substances the cell perishes. This interpretation of the significance of intraplasmatic vacuoles and drops allows us to search for a connection between this cellular change and the gamma globulin content of CSF. It is noteworthy that in both above-mentioned cases, as the morphological changes appeared in the plasma cells an increased gamma globulin content was demonstrated in the CSF, in the following fractional distribution* :

Sz.A. M.A.

~1

~'2

~

~3

~/4

~5

~'6

6.5 10.4

12.5 12.8

13.6 14.3

12.5 9.6

3.9 --

1.6 4.9

-1.2

In these cases the increased gamma globulin content of the CSF and the immunocytological reaction in the reticuloendothelial system (RES) which is simultaneously observed (proliferation of plasma cells, immature plasma-cell forms, vacuoles and drops in the plasma cells), can be interpreted as suggesting that the plasma cells of the CSF may have a role in producing antibody in the CSF. However, the possibility cannot be excluded, that they take part only in the production of certain subfractions. These limited connections are supported by the results achieved by LOWENTHALet al. 11960); they observed the predominance of relatively rapidly migrating subfractions within the increased gamma globulin in cases of multiple sclerosis, in which the acute exacerbations are generally accompanied by a plasmocytic cytological reaction in the CSF. This is corroborated by the data obtained from our patients mentioned above. Our observations bear out the fact that the activation o.f the R E S of the nervous system within the CSF results first of all in an increase of the lymphoidal plasma cells. This is proven by the data given in Table 1 which show that Cco,,n,edonp. 236).. *TheCSFproteinanalysisofourcaseswascarriedoutbyDr.LOWENTHALattheBungeInstitute,Antwerp. J. neuroL Sci. (1967) 4:227-239

234

A. Pt~TER TABLE 1 IMMATURE CELL-FORMS IN THE CSF OF OUR CASES

Patient

Cz°E°

Diagnosis

Non-bacterial meningitis acuta

Cz.Gy.

Non-bacterial meningitis acuta

N.I.

Non-bacterial meningitis Listeriosis

K.J.

S.T.

B.M.

S.Gy.

M.A.

Cs.L.

N.Z. V.I. S.J.

B.I. Sz.A.

S.I. T.L.

Cell count in the CSF (mma )

Cells of blast type (%)

Retieulum cells (O/oo)

Cytological reaction

80

4

l

lympho-plasmocytic

460

2

lymphocytic 150

2 lymphocytic

Non-bacterial meningitis Parotitis

1000

12

Non-bacterial meningitis

360

3

Non-bacterial meningitis Collagenosis

lympho-plasmocytic

lymphocytic leuco-lymphocytic 180

--

Chronic non-bacterial meningitis

720 75

l

Chronic non-bacterial meningitis

670 380

1-3

Non-bacterial meningitis (Sarcoidosis?)

800 160

1

Septic meningitis

3600

2-4

Tuberculous meningitis

1100 80

1-3

Tuberculous meningitis

64

--

3

Tuberculous meningitis

180 10

--

1-2

lympho-leucocytic

Cerebral cysticercosis

360 60

3-4

4-6

plasmo-lymphocytic

Chronic spinal arachnoiditis

170

2-5

1

lympho-plasmocytic

Chronic spinal araclmoiditis

240

2

lymphocytic

lympho-plasmohyperergic

1-8

leuco-lymphocytic leucocytic

--

leuco-lymphocytic lymphocytic

lymphocytic

J. neurol. Sci. (1967) 4:227-239

THE PLASMA CELLS OF THE CEREBROSPINAL FLUID

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J. neurol. Sci. ( 1 9 6 7 ) 4 : 2 2 7 - 2 3 9

236

A. PI~TER

(1) Plasma cells can usually be traced in the CSF of our patients in addition to lymphocytic reactions. (2) During plasmo-cellular invasion of the CSF, one is more likely to see plasmoblast-type cells rather than reticulum cells. (3) In the CSF of our patients lympho-plasmocytic cell forms were more frequent than monoplasmocytic or plasmocellular reticulum cells. We failed to find any connection between the number of plasma cells and the gamma globulin content of the CSF in our patients with subacute sclerosing leucoencephalitis (SSLE). We prepared meningograms from the CSF of 30 patients with SSLE. In none of these cases could immature plasma cell forms or cells with vacuoles in the cytoplasm (i.e. active plasma cells), be found. In six of our patients mature plasma cells could be found in a proportion of 1-5 ~ of total cells in the CSF. In agreement with the observation of KOLAR AND KLAPETEK(1965), in the cytological picture in the CSF of our patients with SSLE monocytic cells were dominant. Considerable oligocytosis should be noted. Electrophoresis was carried out on the CSF of 18 SSLE patients (among these there were 14 in which agar-gel electrophoresis was used). In 15 of them high gamma globulin values were established. In 13 cases the increase of gamma globulin within the CSF was not accompanied by the appearance of plasma cells. In the other five cases the intensity of the plasmo-cellular differentiation was proportional to the increase of the gamma globulin but only to a limited extent. In the CSF of patients with SSLE we succeeded in demonstrating 4-6 subfractions; the relatively slowly migrating ones were dominant (Table 2). It is emphasized both by LOWENTHALet al. (1960) and KOLAR et al. (1965a and b) - - a n d it is suggested by the results of electrophoresis of CSF of our patients-that contrary to the dominance of relatively fast-migrating gamma fractions which is observed in other inflammatory diseases of the CNS, the slowly-migrating gamma globulins predominate in the CSF of cases with SSLE. According to KOLARet al., the slowly-migrating gamma fractions of SSLE are the products of the proteosynthesis of sensitised histiogenic mononuclear cells. Our own data tend to confirm KOLAR'S(1965) suppositions, according to which the defensive activity of the R E S in the cases of S S L E takes place mainly in the tissues of the CNS. Thus, both on the basis of the literature and our own experiences, two forms of humoral defense activity of the nervous system should be supposed, one taking place within the CSF, the other in the tissues. In the former the lymphoidal plasma cells of the CSF may be of decisive importance, producing chiefly an increase in relatively fastmigrating gamma fractions. In the second type of defensive activity of the RES a dominance of relatively slowly-migrating gamma fractions is to be observed; it is not clear at present as to what factors are responsible for this phenomenon. ACKNOWLEDGEMENT I should like to thank Professor Dr. A. LOWENTHAL(Institute Bunge, Antwerp) for his help and advice, without which this work could not have been carried out. J. neurol. Sci. (1967) 4:227-239

THE PLASMA CELLS OF THE CEREBROSPINALFLUID

237

SUMMARY We have found plasma cells in 110 meningograms from among 500 sediments, prepared according to SAYK'S method - - almost exclusively in cases of inflammatory disease of the nervous system. (1) On the basis of a detailed analysis of the plasma cells, we believe that the morphological variants of the plasma cells in the fluid reflect their different stages of maturation, i.e. different phases in their development. (2) In some cases the appearance of immature forms ('blasts') in the CSF, seemed to be connected with the intensity of the plasmocytic reaction. (3) Some of the immature plasma cell forms suggested a reticular and others a lymphoidal origin of the spinal fluid plasma cells. (4) In two cases in which there was an increased g a m m a globulin content in the CSF, we demonstrated intracellular drop-like formations in the plasma cells, a finding which raises the possibility that the cells were immunologically active. (5) In both of our cases in which a high g a m m a globulin content, plasma-cellular invasion, immature cell forms and specific morphological changes suggesting immunological activity were to be found simultaneously--relatively fast-migrating g a m m a subfractions were dominant. (6) In patients with subacute sclerosing leucoencephalitis (SSLE) we failed to find any connection between the plasma cell count and the g a m m a globulin content of the CSF. In the CSF of most of our patients with SSLE the slowly-migrating gammaglobulin subfractions were dominant. (7) On the basis of our data we suppose that two forms of reticuloendothelial system (RES) activity within the nervous system should be distinguished; one may take place in the CSF, the other in the tissues. In the former case the lymphoidal plasma cells of the CSF may be important and may produce relatively rapidly-migrating g a m m a fractions. When immune processes take place in the tissues there is no increase of plasma cells in the CSF and in the majority of such cases the relatively slowly-migrating g a m m a fractions are dominant. REFERENCES

ALZHEIMER,A. (1897) Beitr/ige zur pathologischen Anatomie der Hirnrinde, c. ROTH. ALZHEIMER,A. (1907) Einige Methoden zur Fixierung der zelligen Elemente der Cerebrospinalfltissigkeit, Zbl. Nervenheilk., 30: 449-451. BERNHARD, W. ANI~N. GRANBOtrLAN(1960) Ultrastructure of immunologically competent cells. Cellular aspects of immunity, Ciba Symposion, 91-121. BING,J. ANDP. PLtrM(1937) Serum proteins in leukopenia. Contribution on the question about place of formation of serum proteins, Acta med. scand., 92: 415-428. BJORNEBOE,M. ANDH. GORMSEN(1941) Untersuchungen tiber das Vorkommen von PlasmazeUen bei experimenteller Hyperglobulin~mie beim Kaninchen, Klin. Wschr., 20: 314-316. BISCHOFF, A. (1960) Der derzeitige Stand der Liquorcytodiagnostik, Schweiz. med. Wschr., 90: 479-487. BISCnOFF,A. (1964) Das Vorkommen van Plasmazellen im Liquor cerebrospinalis bei der multiplen Sklerose, Dtsch. Z. Nervenheilk., 185 : 606-617. CAJAL S. R. (1890) Manuelde AnatomiaPatologica General, Barcelona. CERVOS-NAVARRO,J. ANDM. MATIAR(1959) Zur Frage der intrathecalen Regulation und Genese der Liquorproteine, Dtseh. Z. Nervenheilk., 179: 614-638. EnRXCt-I,W. E. (1955) Die cellulhren Bildungsst~tten der Antik6rper, Klin. Wschr., 33 : 315-322. J. neuroL Sci. (1967) 4:227-239

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239

STOBBE,H. (1960). In: H. STOBBE(Ed.), Haematologischer Atlas, Akademie Verlag, Berlin. TH~RY, J. P. (1960) Microcinematographic contributionto the study of plasma cells. Cellular aspect of immunity, Ciba Symposium, 59-91. Voss, G. (1939) Ober die Liquorzytologie des friihesten Stadiums der multiplen Sklerose, Neroenarzt, 12: 470-471. WEDEMEYERH. , (1935) Ober die Zellen im Liquor cerebrospinalis bei der Meningitistuberkulosa, Klin. Wschr., 14: 858-861. WroTE, R. G. (1954) Observation on the formation and nature of Russell's bodies, Brit. J. exp. Path., 35 : 365-376. J. neuroL Sci. (1967) 4:227-239