Mycobacterium tuberculosis can survive and proliferate within phagocytic cells. It may escape the bactericidal effect of the macrophages by preventing the fusion of enzyme-containing lysosomes with phagosomes that contain the organisms. Lipids and waxes of high molecular weight constitute up to 60% of the bacterium’s cell wall and may be responsible for the responses of the host’s tissues to the tubercle bacillus. They may also account for the impermeability of the organism to tissue stains. Tuberculoproteins are responsible for the induction of hypersensitivity and for the reaction of the skin to tuberculin. A substance known as “cord factor” causes the serpentine growth of the tubercle bacillus and can also inhibit leukocyte migration and stimulate granuloma formation.

The host deals with M. tuberculosis principally by the mechanism of cellular immunity. Cell-mediated immunity to tuberculin can be passively transferred to uninfected experimental animals along with living lymphoid cells but not with immune serum. Immunity can also be transferred with the leukocyte extract transfer factor. Although patients with agammaglobulinemia produce no demonstrable antibodies, they can develop delayed hypersensitivity responses and normal resistance to the tubercle bacillus. Patients with defects in delayed hypersensitivity are more susceptible to the disease than persons normal in this respect.

Tuberculosis can affect nearly all of the ocular tissues. Granulomatous uveitis, the lesion most frequently encountered, can be associated with mutton-fat keratic precipitates, Koeppe nodules, and vitreous opacities. Diffuse posterior uveitis can also occur and, although rare with modern treatment, the disease can affect the lids, sclera, cornea, and retina. With the recent increase in tuberculosis in patients with acquired immunodeficiency syndrome (AIDS), the ocular manifestations of tuberculosis are increasing.^1,2,3 Approximately 2% of patients with AIDS or human immunodeficiency virus (HIV) have ocular tuberculosis, and some of these have sight-threatening manifestations, such as choroidal granulomas, subretinal abscesses, and panophthalmitis.^3a

The following three clinical types of leprosy are recognized: (a) lepromatous (nodular) leprosy is characterized by marked deficiency in cellular immunity and extensive infiltration of the tissues with M. leprae; (b) tuberculoid leprosy is distinguished by the preservation of immune responses and the absence of demonstrable bacilli within the tissues; and (c) intermediate or borderline leprosy has features of both the lepromatous and tuberculoid types. Patients with lepromatous leprosy are anergic to the lepromin skin test antigen, to which normal subjects have a positive delayed hypersensitivity reaction. They also fail to develop contact allergy to dinitrochlorobenzene (DNCB) and other contact sensitizers; they have depressed delayed hypersensitivity reactions to common bacterial antigens and they demonstrate prolonged skin allograft survival.^4,5

Patients with lepromatous leprosy have significantly lower than normal levels of circulating T and B lymphocytes, and the T cells in the paracortical regions of their lymph nodes are severely depleted.⁶ Their peripheral lymphocytes show diminished blast transformation in the presence of the mitogen phytohemagglutinin. Animals thymectomized at birth, and therefore lacking cellular immunity, readily develop widespread infections with M. leprae.⁷ The infection is apparently related to the survival of the bacillus within macrophages. Recent electron microscopic studies have shown that the organism can escape from the phagolysosome and remain free in the macrophage cytoplasm.

In contrast to being deficient in cellular immunity, patients with lepromatous leprosy produce normal or greater than normal numbers of antibodies and may even produce autoantibodies. They have above-normal levels of both gamma globulin and the cryoproteins. Thyroglobulin antibodies and rheumatoid factor are found in 50% of patients and false–positive Venereal Disease Research Laboratory (VDRL) test results are seen in about 10%. Lupus erythematosus (LE) cells occasionally appear, and antibodies to both basement membrane and intercellular substances have been found in the skin of infected patients. The similarity between leprosy and the collagen vascular diseases, particularly LE, is indicated by their sharing such clinical manifestations as butterfly facial rashes, arthritis, depressed cellular immunity, and autoantibody production.

In lepromatous leprosy, the lids may show granulomatous inflammation,⁸ and nodules may appear on the face and eyelids. A hyperemic conjunctivitis may develop and may be followed by symblepharon and lid deformities. Corneal nodules, interstitial keratitis, iridocyclitis, and chorioretinitis have also been reported.⁹

Immunity to T. pallidum depends on a complex interaction between humoral and cellular immunity. Several lines of evidence indicate that antibody is important in this infection. Partial immunity develops in the rabbit after the passive transfer of serum from immune animals. Immobilizing antibodies against treponemes can be found in the serum of patients who have had syphilis, especially advanced syphilis. A number of nonspecific or reaginic antibodies are found in the sera of patients who have the disease, and these form the basis of many serologic diagnostic tests. Immune complex deposition can play a role in the nephropathy associated with secondary syphilis in adults, and IgG may be found along the glomerular basement membrane in patients with congenital syphilis.¹⁰

Delayed hypersensitivity directed against treponemal antigens is absent in primary and early secondary syphilis; it develops late in the secondary disease and is found regularly in latent and tertiary disease. Because syphilis progresses through the primary and secondary stages despite the presence of antibodies that immobilize treponemes, it follows that antibodies developing during the course of an infection, at best, are only partially protective.

When viewed microscopically, the typical lesion of syphilis is a granulomatous inflammation. Granulomas, which contain reticuloendothelial cells (including epithelioid and giant cells), are thought to represent an immune response to such poorly soluble substances as foreign bodies, insoluble antigens, and microorganisms that cannot be easily eliminated. Granulomatous reactions clearly differ from typical delayed hypersensitivity reactions: their onset is much slower, and they may require weeks or even months to develop. Many granulomatous lesions are accompanied by vasculitis, suggesting that an associated immune complex disease may exist.

Although the host’s defenses against tularemia are not fully understood, cell-mediated immunity appears to be important. Immunity is associated with (a) a delayed hypersensitivity skin reaction to tularemia skin-test antigen, and (b) the greater-than-normal ability of rabbit macrophages to kill F. tularensis. In vitro tests for cell-mediated immunity are present in sensitized individuals. Inactivated vaccines have no protective effect, but a live, attenuated strain of the organism can protect both humans and animals. No evidence suggests that antibodies are protective in tularemia.

Brucella has a predilection for the reticuloendothelial system. Once ingested, the organisms are rapidly taken up by neutrophils and transported to the histiocytes of the liver, spleen, and lymph nodes. There, they enter a period of prolonged intracellular residence. They can remain intracellular for several weeks (rarely for months) while the phagocytes containing the organisms form noncaseating granulomas. Clinical symptoms occur when organisms are released from infected reticuloendothelial cells.

Immunity to Brucella seems to be cell mediated. Delayed hypersensitivity develops during experimental infection. The skin test lacks specificity, however, and has been discontinued for routine use in the United States.

Although antibodies in Brucella infection are not protective, agglutinating and complement-fixing antibodies can be measured. An IgA antibody can act as a blocking factor and produce spuriously low agglutinin levels, but interference by this factor can be avoided by using a Coombs’ test. Antibody measurement is important in the diagnosis of brucellosis, because the organism is fastidious and culturing is difficult.

The V-Z virus is neurotropic and produces a skin rash with a dermatome distribution. Most herpes zoster infections are caused by a reactivation of latent V-Z virus residing in the dorsal root of a ganglion. This usually occurs at a time when the host’s immunity is in some way compromised. The reactivated virus can travel along the nerve axons and produce the characteristic vesicular lesion of the skin in accordance with the distribution of the nerve. Infection can also follow re-exposure of the host to the virus by contact with a patient who has either chickenpox or zoster. In neither event can the affected immune-deficient individual respond adequately to ward off the viral infection.

It has been shown that varicella can be prevented by passive immunization with antibody to V-Z virus. The role of antibody in the prevention of zoster, however, and in the eventual recovery from either zoster or varicella is somewhat less clear. Hope-Simpson²⁷ has suggested that a critical antibody level exists above which an individual is protected from latent virus in neuronal tissues, and that this level can be maintained by endogenous or exogenous stimulation by viral antigens.

Complement-fixing antibody usually appears early in the course of V-Z infection, and some observers have speculated that patients lacking such antibody early in the course of zoster are more likely to have disseminated zoster infection. Although patients with disseminated zoster do not synthesize detectable levels of complement-fixing antibodies until 2 or 3 weeks after the disease begins, some of them have been shown to have V-Z antibody when tested by a new, more sensitive method. By this method (immunofluorescence), it is possible to detect antibodies to membrane antigens of cells infected with the virus and to show a prompt rise in IgA, IgG, and IgM in both localized and generalized zoster.²⁸ Dissemination can occur even in the presence of high levels of serum antibody. This means that a brisk serum antibody response to V-Z virus does not necessarily alter the course of the disease.

It has long been suspected that cellular immunity is important in the recovery from infection with V-Z virus.²⁹ Patients with cell-mediated immunity deficiencies are more susceptible to zoster than patients with humoral immune deficiencies. Depression of cellular immunity from malignancy or treatment with immunosuppressive drugs also predisposes to the development of zoster. In vitro studies have shown that leukocytes from donors immune to varicella are more efficient in inactivating V-Z virus than leukocytes from donors susceptible to varicella.³⁰ The leukocytes from the susceptible patients fail to reduce the V-Z virus titer. Thus, individuals who recover from V-Z virus infection have specific cell-mediated immunity against the virus. They seem also to have high local levels of interferon.

Approximately 8 days after an inoculation of the skin with vaccinia virus, a delayed hypersensitivity reaction develops at the inoculation site.³¹ The vaccinia virus contains antigens that cross-react with smallpox virus, protecting the vaccinated individual from smallpox. Vaccination of normal subjects produces no systemic disease unless the patient has been compromised.

The immune response to vaccinia virus is the result of an interaction between antibody, cell-mediated responses, and interferon. A healthy, immunocompetent subject responds to intradermal vaccination with a “primary take”: the host’s immune defenses eradicate the virus at the site of inoculation. Subsequent revaccination in the same subject produces a milder skin reaction that peaks in 4 or 5 days. This reaction is probably caused mainly by cell-mediated immune responses to the virus. Subjects with severe defects in cellular immunity almost always have a fatal response to smallpox vaccination. Subjects with defective antibody responses can develop severe necrotic skin reactions (vaccinia gangrenosum), but this can be treated successfully with vaccinia immune globulin or the drug thiosemicarbazone. These preparations, however, cannot prevent a fatal response to smallpox vaccination in patients with T-cell defects. It would seem, therefore, that both humoral and cellular immunity are important in the control of vaccinia virus infection. It may be that antibody participates in the reduction of the antigen load (i.e., the mass of virus particles), and that failure to do so may result in temporary immune paralysis of the T-cell system. If the T-cell system is inoperative, the virus will apparently not be eliminated despite the presence of antibody.

Immunization of rabbits with vaccinia virus vaccine by the intranasal route results in the appearance of IgA antibody activity in tears.³² If the vaccination is intradermal, however, the antiviral activity of the tears is associated with IgG. IgG is also the predominating serum immunoglobulin found in immunized animals. Antibody titers in both tears and serum can be raised by the interferon inducer poly I:C. Vaccination by either the intradermal or the intranasal route results in reduced shedding of the virus and a reduction in the rabbit’s clinical disease.³³ High levels of serum-neutralizing antibody can be correlated with mild illness, but tear antibody is apparently not related to either illness or virus shedding. The lack of protection by neutralizing antibody in the tears suggests that the cellular immune mechanism plays a prominent role in vaccinia virus infection.

After the inoculation of the rabbit cornea with vaccinia virus, the cells within the deep layers of the epithelium are the first to show infection and to undergo degeneration.³⁴ Viral replication is thought to occur within the stromal keratocytes.³⁵

The fetus is most susceptible to the effects of the rubella virus from day 20 to day 40 of gestation. The mechanism responsible for the malformations is not completely understood. It is believed that death of the infected cells, a change in rate of cell growth, or perhaps both of these mechanisms are important. The reason for the virus persistence in the fetus is not understood. Endogenous IgM antibodies and maternal IgG antibodies are present at birth, and the antibody responses of the fetus are apparently intact. Fetal cellular immunity is depressed, however, and this may be a factor in the inability of the fetus to clear virus from the tissues.

In postnatal rubella infection, antibodies to the virus increase rapidly, reaching maximal titers in 7 to 10 days. IgM antibody can be detected for approximately a month, but IgG antibody persists for many years.³⁷ Antibodies to rubella virus can be assayed by such techniques as hemagglutination inhibition, neutralization of virus infectivity, complement fixation, indirect immunofluorescence, and immunoprecipitation. All of the assay methods (except complement fixation) yield similar results, with the titers peaking within 2 weeks and then gradually decreasing. Antibodies usually remain detectable for life, and individuals with antibodies in their sera are believed to be immune from reinfection.