9. The toxic agent is destroyed or rendered inactive in alkaline solution by a typical hydrolytic ferment, pancreatin.
10. Incomplete experimental evidence suggests that the activity of the toxic agent may be heightened by a possible lytic action of the blood serum of a sensitive individual, and that the sensitive serum itself may contain the toxic agent in solution.
These results, as far as they go (omitting No. 10), accord with Langer"s except on the point of alcoholic solubility and the effect of acids. The actual nature of the toxic agent in the black-fly is left a matter of speculation.
The following working theories have suggested themselves to the writer.
First, the toxin may be, as Langer believes in the case of the bee, an alkaloidal base, toxic as such, and neutralized after injection by antibodies produced for the occasion by the body. In such a case the view that a partial local fixation of the toxin occurs, which prevents its immediate diffusion, is acceptable. Through chemotactic action, special cells capable of breaking up the toxin into harmless elements are attracted to the scene. Their function may be, on the other hand, to neutralize directly, not by lysis. This would explain the role of the eosinophiles in the black-fly lesion. If their activities be essential to the destruction or neutralization of the toxin, one would expect them to be most numerous where there was least reaction. This would be at the site of a bite in an immune individual. A point of special interest for further investigation, would be the study of such a lesion.
Second, it is conceivable that the injected saliva of the fly does not contain an agent toxic as such. It is possible, that like many foreign proteins, it only becomes toxic when broken down. The completeness and rapidity of the breaking down depends on the number of eosinophiles present. In such a case immunity should again be marked by intense eosinophilia.
[Ill.u.s.tration: 173. Fifth day mature lesion. Lower power drawing showing papillary dema and infiltrate in the region of the puncture. After Dr.
J. H. Stokes]
Third, lytic agents in the blood serum may play the chief role in the liberation of the toxic agent from its non-toxic combination. An immune individual would then be one whose immunity was not the positive one of antibody formation, but the negative immunity of failure to metabolize.
An immune lesion in such a case might be conceived as presenting no eosinophilia, since no toxin is liberated. If the liberation of the toxin is dependent upon lytic agents present in the serum rather than in any cellular elements, a rational explanation would be available for the apparent results (subject to confirmation) of the experiment with sensitive and immune sera. In this experiment it will be recalled that the sensitive serum seemed to bring out the toxicity of the ground flies, and the serum itself seemed even to contain some of the dissolved or liberated toxin. The slowness with which a lesion develops in the case of the black-fly bite supports the view of the initial lack of toxicity of the injected material. The entire absence of early subjective symptoms, such as pain, burning, etc., is further evidence for this view. It would appear as if no reaction occurred until lysis of an originally non-toxic substance had begun. Regarding the toxin itself as the chemotactic agent which attracts eosinophiles, its liberation in the lytic process and diffusion through the blood stream attracts the cells in question to the point at which it is being liberated. Arriving upon the scene, these cells a.s.sist in its neutralization.
The last view presented is the one to which the author inclines as the one which most adequately explains the phenomena.
A fourth view is that the initial injection of a foreign protein by the fly (i.e., with the first bite) sensitizes the body to that protein. Its subsequent injection at any point in the skin gives rise to a local expression of systematic sensitization. Such local sensitization reactions have been described by Arthus and Breton, by Hamburger and Pollack and by Cowie. The description of such a lesion given by the first named authors, in the rabbit, however, does not suggest, histopathologically at least, a strong resemblance to that of the black-fly. Such an explanation of many insect urticariae deserves further investigation, however, and may align them under cutaneous expressions of anaphylaxis to a foreign protein injected by the insect. Depending on the chemical nature of the protein injected, a specific chemotactic reaction like eosinophilia may or may not occur. Viewed in this light the development of immunity to insect bites a.s.sumes a place in the larger problem of anaphylaxis.
[Ill.u.s.tration: 174. Experimental lesion produced from alcohol-fixed flies, dried and ground into a paste with glycerin. After Dr. J. H.
Stokes]
SUMMARY
In order to bring the results of the foregoing studies together, the author appends the following resume of the clinical data presented in the first paper.
The black-fly, _Simulium venustum_, inflicts a painless bite, with ecchymosis and haemorrhage at the site of puncture. A papulo-vesicular lesion upon an urticarial base slowly develops, the full course of the lesion occupying several days to several weeks. Marked differences in individual reaction occur, but the typical course involves four stages.
These are, in chronological order, the papular stage, the vesicular or pseudovesicular, the mature vesico-papular or weeping papular stage and the stage of involution terminating in a scar. The papule develops in from 3 to 24 hours. The early pseudovesicle develops in 24 to 48 hours.
The mature vesico-papular lesion develops by the third to fifth day and may last from a few days to three weeks. Involution is marked by cessation of oozing, subsidence of the papule and scar-like changes at the site of the lesion. The symptoms accompanying this cycle consist of severe localized or diffused pruritus, with some heat and burning in the earlier stages if the dema is marked. The pruritus appears with the pseudovesicular stage and exhibits extraordinary persistence and a marked tendency to periodic spontaneous exacerbation. The flies tend to group their bites and confluence of the developing lesions in such cases may result in extensive dema with the formation of oozing and crusted plaques. A special tendency on the part of the flies to attack the skin about the cheeks, eyes and the neck along the hair line and behind the ears, is noted. In these sites inflammation and dema may be extreme.
A distinctive satellite adenopathy of the cervical glands develops in the majority of susceptible persons within 48 hours after being bitten in the typical sites. This adenopathy is marked, discrete and painful, the glands often exquisitely tender on pressure. It subsides without suppuration.
Immunity may be developed to all except the earliest manifestations, by repeated exposures. Such an immunity in natives of an infested locality is usually highly developed. There are also apparently seasonal variations in the virulence of the fly and variations in the reaction of the same individual to different bites.
Const.i.tutional effects were not observed but have been reported.
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