From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Th1/Th2 in Chronic Infections
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6428
Organization: unspecified
Date: Sun, 8 Nov 92 11:29:33 PST

Fitzgerald has a very interesting hypothesis concerning chronic 
infections such as predominate in AIDS. If this hypothesis holds true 
for viral infections such as HIV, it could explain the inability of the 
immune system to clear it. If immunoregulation switches to Th2 prior to 
viral clearance by Th1 after initial acute infection, HIV would become a 
chronic infection. Research has already been done on the chronic 
infections mentioned in the article, and it appears to support what is 
already known about their pathogenesis.
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Fitzgerald, Thomas J., Department of Medical Microbiology and 
Immunology, School of Medicine, University of Minnesota, Duluth, 
Minnesota 58812. 

The Th1/Th2-Like Switch in Syphilitic Infection: Is It Detrimental?

INFECTION AND IMMUNITY, Sept. 1992; 60(9):3475-3479.              

From page 3475.

CHRONIC INFECTIONS

Immunologic responses are rigorously controlled by complex regulatory 
pathways. One way to study these pathways is to examine their defects in 
chronic diseases, a newly developing area of immunology. In acute 
infections, functional activity is rapidly stimulated to eradicate the 
invading organisms and then quickly down-regulated to minimize 
inadvertent damage to those tissues. In chronic infections, organisms 
have evolved mechanisms to partially evade immune defenses. There are 
interesting parallels for chronic diseases caused by leishmaniae, 
trypanosomes, schistosomes, filariae, Mycobacterium leprae, 
Mycobacterium tuberculosis, Mycobacterium intracellulare, rickettsiae, 
and brucellae. An early acute stage of localized infection is typical. 
Numbers of organisms rapidly increase, hose defenses are effectively 
stimulated, and most, but not all, of the organisms are eliminated. 
During this acute stage, a transient concomitant immunity is apparent 
and animals cannot be reinfected if injected at distant sites. Clearance 
of organism involves delayed-type hypersensitivity (DTH) activation of 
macrophages. At some point, however, macrophage suppressive activity 
develops. This suppression involves prostaglandin E2 (PGE2), is specific 
for that chronic disease without causing generalized immunosuppression, 
and is transient. Exogenous gamma interferon reveres this suppression 
and restore macrophage activation, indicating a defect at the macrophage 
level. Finally, the chronic stage also involves elements of 
autoimmunity.

One key question applies to each of these chronic infections: how do 
some of the organisms escape the initial onslaught of macrophage killing 
that resolves the acute stage of infection? Immune evasion could result 
from a number of different mechanisms. A newly emerging concept involves 
premature down-regulation of the appropriate host defenses. As the acute 
stage clears, immune responses are shut off too early, leaving a few 
residual organisms. These slowly multiply, giving rise to chronic 
disease. PGE2 plays an important role in normal down-regulation of 
different immune responses. In certain infection, such as those caused 
by M. leprae, M. intracellulare, and Rickettsia tsutsugamushi, 
macrophages oversecrete PGE2. This accelerates the process of normal 
down-regulation. PGE2 also selects for Th2 responses. In leishmanial 
infections, the acute stage is resolved through activation of Th1 
lymphocytes (and secretion of gamma interferon for DTH); these cells, in 
turn, are down-regulated, Th2 lymphocytes predominate (interleukin-4 
[IL-4]), antibodies accumulate, and chronic disease develops. In 
trypanosomal and schistosomal infection, IL-10 and IL-4 from Th2 
lymphocytes depress the Th1 responses; in the absence of effective DTH, 
chronic disease develops. In the last examples, early down-regulation of 
Th1 activity is advantageous to the parasites.

The purpose of this review is to relate Treponema pallidum to these nine 
other chronic diseases, with specific emphasis on immunoregulation 
during early syphilitic infection. Regulation mediated by anti-      
idiotypes, which may play an important role much later in syphilitic 
infection will not be discussed. Baughn's group has made some 
interesting observations; they have suggested that anti-idiotypes 
reflect an attempt by the host to minimize autoimmune phenomena that 
occur later in infection.

From pages 3477-78:

SUMMARY

Organisms that cause chronic diseases have evolved mechanisms to evade 
those immune defenses that resolve the acute stage of infection. Much is 
to be learned by specifically identifying the mechanisms underlying 
these evasive strategies. Important new insights will emerge in terms of 
immunoregulatory pathways. This in turn will facilitate vaccine 
development. A good example is leishmania infection. The acute stage of 
this disease is resolved by DTH-macrophage activation. Leishmanial 
components preferentially activate Th2 lymphocytes. As a consequence, 
Th1 effects are minimized and infection exacerbated leading to 
chronicity. To overcome this negative tendency, leishmanial vaccines are 
administered in combination with exogenous gamma interferon. This 
selects for Th1 predominance and generates protective immunity.

Syphilis exhibits many parallels to the other nine chronic diseases 
mentioned above. Similarities include an acute localized stage that 
readily heals, early clearance via DTH-macrophage activation, transient 
concomitant immunity during acute infection, development of macrophage 
suppression through PGE2 down-regulation, beneficial effects of 
exogenous gamma interferon, and elements of autoimmunity. Some of the 
complexities of immunoregulation during treponemal infection has just 
begun to be unraveled. It will be important to develop further insight 
into the Th1/Th2 switch especially as it relates to chronicity. 
Macrophages seem to be intimately involved in the mechanics of this 
switch, and their specific role need further clarification. Whatever is 
learned about syphilis, as well as other chronic infections, will 
contribute to a better understanding of the generalized pathways of 
immunoregulation.
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