ABSTRACT
Reassessing the role of Bordetella toxins in inducing experimental allergic encephalitis, revisited the pertussis physiopathology of newborn from hyperimmune mother and the pathology from immune complexes, I searched for anti-Bordetella antibodies in different groups of patients with Multiple Sclerosis (MS).
The results demonstrate that in the 90 % of 40 patients with chronic-evolutive MS, an infection by Bordetella Pertussis is taking place and that in the 94,57 % of 92 MS-patients, not selected for clinic form, there are abnormal levels of antipertussis antibodies in the serum.
This suggest that in MS:

• the environmental factor is Bordetella;
• the individual factor, sine qua non, is a muco-ciliar barrier defect;
• a specific antibiotic treatment is mandatory to stop the course of the disease and prevent severe disability.

• the Lipopolysaccharide (LPS) fully covers the external membrane;
• the toxin PT, or Lymphocytosis Promoting Factor (LPF), is an integral part of the cell wall. B.Parapertussis and B.Bronchiseptica do not produce LPF 15 (the producer gene is silent 54) .

• with non-immunologic mechanism, irreversibly activate all the immunocompetent cells;
• are the most powerful Thymus-indipendent aspecific polyclonal activator that is known;
• trigger off the reaction between macrophages and T-helper lymphocytes (gamma-interferon + 2-interleukin production);
• arm the macrophages;
• they interfere with transduction of membrane signals and with transmembrane ionic fluxes of neuroepithelia (ependyma, astrocytes, oligodendrocytes); by protracted action, they make T-lymphocytes and macrophages cytotoxic towards allogenic, syngenic and of the same individual splenic cells (autocytotoxicity).

• they stimulate the production of specific antibodies (normal immune response);
• with non immunologic mechanisms, they activate T-lymphocytes till they become autocytotoxic, they arm macrophages (adjuvant action);
• BB-toxins + specific antibodies form ICC which, precipitating, offend the haemato-encephalic barrier (peculiar action, sine qua non) and put T-lymphocytes and macrophages in direct contact with the neural tissue: a delayed hypersensitivity towards astrocytes, oligodendrocytes and myelin springs up (see after).

SUBJECTS - METHODS - RESULTS
I did not check healthy subjects as, in my preceeding research18, I had found negative all the healthy controls and as in a research ^{( see note 19 )} on 3.875 healthy subjects, from 5 italian regions, in young people from 17 to 19 years of age, in E.L.I.S.A., anti pertussis-toxin IgG were absent in the 95 % of the cases.

1^st group
In patients affected by definite chronic-evolutive MS (C-E MS), I could search, in E.L.I.S.A., for the antibodies of the acute phase of pertussis infection, that is anti filamentous haemoagglutinin (FHA) and anti pertussis-toxin (PT) IgA. According to the quantity, specificity and class of the antibodies found and in accordance with the interpretative scheme enclosed in the diagnostic kit, the Laboratory ^{( see note 20 )} declares "absence of infection" in the subjects with O.D. of anti-FHA and anti-PT IgA below 0.30 (characteristic levels of children who have not contracted pertussis and have not been vaccinated; normal levels in grown-ups after approximately ten years from infantile pertussis); it mentions "taking place or very recent infection" when at least one of IgA has O.D. equal or above 0.30. With this method I studied 40 C-E MS patients: in 4 patients there was "absence of infection" = 10 %; for 36 patients, the Laboratory spoke about a taking place or very recent infection.

2^nd group
In E.L.I.S.A., searching as well for the total amount of anti-Bordetella IgG and IgM (besides anti-FHA and anti-PT IgA and IgG) with the formula: [patient’s optic density / cut-off optic density] x 10 = VE (extinction’s units), in 88 MS patients, not selected according to their clinic form and treatment, asking to the Laboratory for the optic density (O.D.) of the sample and of the cut-off, I found:

• in 63 patients, taking place infection (68,48 %);
• in 24 patients (negatives for anti-FHA and anti-PT IgA), abnormal titres of total anti-BB IgM;
• in 5 patients, absence of all the tested classes of antipertussis antibodies.

DISCUSSION
Direct micro agglutination is given only by the intact bacterium: it demonstrates recent contagion ^{( see note 11 )}. IgG express a secondary immune response to the systemic antigenic stimulus. The natural antipertussis immunity (acquired with the infantile disease) is local, mucosal; the IgA antibodies may intervene inhibiting the bacterial adhesion , but the real immunity (protective) is cell-mediated and is characteristically left, above all, to granulocytes (rather than to macrophages) ^{( see note 11 )}. In normal subjects, the antipertussis immunity, humoral and cell-mediated, disappears after 10-15 years, and therefore, in adults there are few or no antipertussis IgG. If the muco-ciliar barrier (MCB) is intact, reinfections by BB remain a "surface disease" ^{( see note 21 )}: the rapid reclamation of the respiratory mucosa limits the production and the passage of toxins into blood and there are not relevant systemic reactions. A genetic susceptibility to MS has been connected 22 to an alteration of the gene for basic myelinic protein (BMP) or of an adjacent locus, on chromosome 18. But chromosome 18 alterations or deletions have been repeatedly demonstrated associated with an IgA deficit from a secretory gene defect ^{( see note 23 )} (lymphocytes regularly produce IgA, but they are not able to secrete them).

This genetic defect causes a deficit of secretory-IgA, therefore, a defect of MCB, so, if a reinfectin from B. Pertussis occurs, there is a protracted passage of pertussis toxins into blood and consequent systemic effects. The great importance of MCB is confirmed by the observation that 24 while in European, North-American and Australian populations there is one IgA deficit every 350-500 individuals; in Japan there is one IgA deficit every 15000 individuals and Japan is the country less hit by MS all over the world 1 . A MCB defect may be: primitive, secondary, transient (viral infections), even only specific (lacking of specific IgA-S); it may be sustained by inflammatory alterations of respiratory mucosae (chronic sinusitis) 25 . In MS patients, the presence of agglutinant antibodies (anti fimbrial antibodies) testifies a reinfection from BB taking place or very recent; the presence of high titres of IgG (secondary immune response) proves an abnormal (repeated or protracted) passage of pertussis toxins in blood, therefore, a defect in MCB.

The first manifestation of MS is very often an optic neuritis (ON); but it is known that "temporary or permanent blindness is a very rare complication of pertussis; it can be associated with signs indicating optic neuritis and retinal ischaemia, or it can be secondary to cerebral damage ^{( see note 12 )}". The optic nerve anatomy ^{( see note 27 )} explains its frequent involvement in MS. In fact: the tortuosity of the ophtalmic artery and vein, the length of the nerve and of its blood vasa (rather greater than the distance between optic foramen and rear pole of the glene), the disposition of ciliary and of retinal vasa, the path of the nerve in an inextensible canal (optic canal), make the post-capillary venules of the optic nerve a vasal net with very slow flow (ulteriorly slowed down by the movements of the glene, during which the curves of the italic-S of the nerve narrow). In the ICC precipitation we have ^{( see notes 28, 29 )}: leucocytes and plasmocytes aggregation, capillary necrosis, haemorrhages, anaphilotoxins and cytokines release; in reply to the bacterial stimuli (LPS) and per cytokines action, the vasal endothelium exposes the adhesion molecules 30 , which "hook" the fimbrial adhesins, always associated 10 with the LPF pertussis toxin; infiltration of ICC under the endothelium (that is, serious alteration of HEB) ^{( see notes 31, 32 )}. The initial lesion of the optic nerve is due to type III immunoreactions; at the first moment at least there are no cell-mediated mechanisms. Adhesion molecules ^{( see note 29 )} are normally generated by the vasal endothelium in reply to bacterial stimulus (LPS) and/or per cytokines action. They constitute "adhesion receptors" to which phagocytes "adhere", having become "sticky" for chemiotactic stimulus. The quick transition from "adherence" to "non-adherence" allows the immunocompetent cells to carry out the double role of surveillance and reply (adherence) or non-reply (non adherence), depending on local necessities. The adhesion receptors are expressed not only by the immune system but also by other systems, including the CNS ^{( see note 30 )}.

Adhesion molecules always intervene in the ICC precipitation; but, in MS, the pathologic process is precipitated by the activation of the immunocompetent cells operated by Bordetella toxins. Adhesion molecules are a physiologic aspect of the type III immune reaction, that damages the HEB; they are "effect", not "cause". About the role of astrocytes, I think it`s sufficient to remember that in cerebral vasa the adventitia is not composed of connective tissue but of astrocytes, that are therefore integral part of the vasal wall. In MS the initial damage to haemato-encephalic barrier and to the perivenous nervous tissue is due to ICC-BP precipitation into the small cerebral vessels; only after these lesions, T-limphocytes and macrophages, preliminarily activated and made autocytotoxic by Bordetella toxins, get in touch with cerebral antigens; but, it is important to know that, if lesions were not too much serious and if ICC production ceases, lesions regress and they tend to disappear completely ^{( see note 29 )} (frequent restitutio ad integrum, in O.N.). In MS, at patch level there is an essentially peri-venular infiltration of lymphocytes, plasmocytes, macrophages, immunoglobulins, immune complexes and Complement ^{( see note 33 )}; Immune complexes circulating in serum and in liquor were described in more than a half of MS patients 34. Endocerebral deposits of immune complexes are easy to elute ^{( see note 35 )}: they are not constituted by antibodies fixed to cerebral tissue ^{( see notes 34, 35 )}. To the periphery of the patch there is a great afflux of CD8+ T-limphocytes; serum has myelinotoxic activity; in presence of BMP or of cerebral antigens, serumal and liquoral T-limphocytes undergo a blast transformation; cutaneous tests for Koch-type hypersensitivity to BMP and to white human cerebral substance are negative ^{( see note 33 )}.

The only immune reaction which is compatible with all these findings is Jones-Mote`s basophil, transient, delayed hypersensitivity (J-M`s d.h.) ^{( see notes 36, 37 )}. J-M`s d.h. can be transmitted either by lymphocytes or by serum (myelin-toxicity in MS);

1. it gives a weak and transient cutaneous reaction (beginnig around the 8th day and disappearing in 1-4 weeks, as soon as the antibodies titre rises);
2. it does not give nodes like the tuberculin reaction but simple erythema (intradermo reaction negativity in MS);
3. it takes place in antigen site and it is characterized by the strong prevalance of CD8+ T-lymphocytes;
4. after the first phase, which is essentially cell-mediated, it produces antibodies in loco (this explains the intra-thecal IgG production and "the abnormal intra-thecal immune activity", characteristics of MS).

The possibility, often taken into consideration in literature, that several infective factors concur to the origin of the disease, derives from the ascertainment that in MS:

• one may find, in the same patient, high titres of serum and liquor antibodies against several infective agents (above all viral agents);
• post-infective relapses are commonly observed.

The clinical forms of the disease depends on the relationship that is established between Bordetella and Host. The principal factors related to BB are:

1. protracted survival or stable mucosa colonization;
2. bacterial transformation from S-phase to R-phase.

• They regulate the potassium balance in the extracellular space;
• They have a ionic system for the transport and the exchange in pairs of Na and H and of Cl and bicarbonate;
• They contribute to the mantenance of the haemato-encephalic barrier integrity (in small cerebral vessels the adventitia is constituted by astrocytes, not by connective);
• They perform the role of Antigen Presenting Cells (APC);
• They produce interleukin-1 as an answer to phlogogenic stimulus.

CONCLUSIONS
The Multiple Sclerosis is a toxi-infective disease from barrier defect: the environmental factor is constituted by Bordetella; the individual factors are the muco-ciliar barrier defect and the astrocytes phenotype (II class Ag-HLA producers).

In individuals with a primitive or secondary MBC defect, after reinfection by Bordetella, we can have ^{( see note 40 )}:

MS with igg: transient passage of toxins into blood, delayed reclamation of respiratory mucosa.. There is production of IgG and ICC, which, precipitating trigger off an attack. In the free intervals anti-BB IgG and average-low ICC levels are found in serum.This is the MS with IgG, remittent.

MS with igm: colonization of mucosas (BB from S-phase to R and L-phase); protracted passage of toxins into blood. LPS action prevails: protracted IgM and ICC production; autocytotoxic T-lymphocytes, average-high levels of ICC and/or anti-BB IgM (often, IgM > IgG) are found in blood; ICC level and size, the elective tropism (fimbrial adhesins) and the anatomo-functional peculiarities of cerebral circle (already mentioned) induce their periodic, frequent precipitation. Because of the characteristics of Jones-Mote’s hypersensitivity (cell-mediated reactivity stops when the titre of specific antibodies increases) and of the cyclical inhibition of antibodies production by ICC, there can be more or less long free intervals; also because of spheroplasts reversibility to S-phase, the disease nourishes itself (MS with IgM, chronic-evolutive with free intervals).

Seronegative-MS: In subjects with mucosa colonization by BB (heavy vascular damages do not regress rapidly and completely), two conditions are possible: a) new toxins and residue and/or neoformed antibodies form immune complexes that immediatly precipitate into previous cerebral lesions (anti-pertussis antibodies and ICC are not found in serum); b) lacking antibodies, new toxins go and fix themselves to neuroepithelia (elective tropism); with antibodies, also locally neoformed, they form immune complexes where the lesion is. In seronegative MS, the patches are always active; the T-lymphocites and the macrophages are autocytotoxic. In serum, there are not ICC nor anti-BB antibodies at positive levels for pertussis. The finding of IgM titre >= 4-5 VE, in any case higher than the one of IgG, is not always present but indicative. This is the Seronegative-MS, chronic-evolutive without free intervals.

If we don’t find anti-B Pertussis antibodies after general and local (nasal aerosol) antibiotic treatment, considering that there isn’t cross-immunity between the different species of BB, we should search for anti-B.Parapertussis and for anti-B.Bronchiseptica antibodies. In fact:

• pertussis is usually referred to B.Pertussis;
• but in some geographical area (Mexico and Eastern Europe) the 17-30 % of the cases is caused B.Parapertussis (frequent as well in Denmark ^{( see note 11 )}), against which, in many regions, USA included, the most part of the population has specific antibodies circulating ^{( see note 48 )}.
• In Western Europe, B.Pertussis prevails, but the 5-10% of the cases is due to B.Parapertussis;
• a lower percentage is caused by B.Bronchiseptica ^{( see note 15 )}.

ETIOLOGICAL DIAGNOSIS AND DIAGNOSIS OF THE CLINICAL FORM
The pathognomonic diagnosis of MS and of its clinical form requires:

• the searching for anti-FHA and anti-PT IgA and IgG;
• the searching for total anti-BB IgG and IgM in E.L.I.S.A. (the Complement Fixation Method is not very sensitive: there can be false negatives in presence of CIC, of IgA, of endotoxins).

In MS we can find:

• in the remittent forms (R-R), positive IgG and IgM with VE less then 4;
• in the chronic-evolutive forms:
  1. positive IgG and IgM;
  2. only positive IgM;
  3. only positive IgG, but IgM are not over 4 VE units;
  4. both classes of immunoglobulins are "negative" but the level of IgM is very closed to the one of IgG.

TREATMENT
The MS specific etiological treatment is constituted by the protracted administration of Erythromycine to reclaim rhino-sinusal mucosae from B. Pertussis.
Naturally, the antibiotic treatment will stop the evolution of the disease (it will not make the consolidated lesions regress), so the more precociously it will start, the more effective it will be. The erythromycine does not have any important contraindications or fusses, as it can be used during pregnancy. At the beginning of the treatment, an aggravation of the neurologic symptomatology is probable for the onset of a Jarisch-Erxheimer reaction: the bacterial lysis involves an increase of toxaemia, an increase of ICC containing pertussis toxins, the precipitation of these ICC at the level of small cerebral vessels, the renewal of the MS disease. This reaction may arise even 20-40 days after the beginning of the antibiotic treatment; but the new lesions will completely regress adding some bolus of cortisone to erythromycine, as if it were by all means an attack.

PROPHYLAXIS OF RELAPSES
In all cases, for the enormous diffusion of Bordetella, sooner or later a reinfection, which is impossible to forecast, may occur.
In the patient who is undergoing an antibiotic treatment, the reinfecting bacterial strength will not attach; the quantity of toxins will be small and it will not be repeated in time; the patient may have a breakthrough of the disease, but, also in this case, the new lesions will completely regress after a few days of treatment with cortisone.
Once the mucosae are reclaimed, an effective prophylaxis of relapses will be achieved following the same rules that are followed for the prophylaxis of the rheumapyra in subjects allergic to penicillin: administering erythromycine for years ^{( see notes 49, 50, 51, 52, 53, 54 )}. «The optimal length of the continuous antibiotic prophylaxis has not being determined yet. Some Authors suggest to continue the prophylaxis "indefinitely", probably for lifetime ^{( see note 54 )}». In any case, «In patients who are affected by the rheumatic disease without carditis after the age of 18, a period of prophylaxis at least of five years is recommended ^{( see note 55 )}». If, in the prophylaxis of the rheumatic disease, even without carditis, the erythromycine is to be administered for several years, the same can be and is to be done to prevent the severe disability so often caused by MS. In presence of chronic nasosinusitis (very frequent and often ignored), thiamphenicol per nasal aerosol (15-20 days) can be associated to the macrolide per os. Beta lactamics are inadvisable, because they facilitate BB transformation in R-forms and in spheroplasts ^{( see note 56 )}.

THANKS
The anti-Bordetella antibodies investigation I mentioned here, was done by Ospedale Civile "San Salvatore" of Pesaro laboratory. I want to thank for the relevant cooperation:

• the Executive Unit manager, Dr. Gabriele Rinaldi;
• the Serology and Immunology Department manager, Dr. Marcello Acetoso who took care of the investigations;
• the Laboratory's technicians for the competence and availability
• the Administrative and Chief Surveyor's Office staffs

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