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292 Part III Immunologic Basis of Hematology

and humans. These findings highlight a genetic basis for recognizing 1 2 3
self-molecules in autoimmune diseases and suggest new therapeutic HPA-1 a HPA-1 a HPA-1 b b
targets that are currently being explored. specific A specific B specific B HPA-1
specific
T cell B cell T cell B cell
Environmental Factors
Alloantibody A Autoantibody B
Environment plays a role that is at least as important as genetics. response B response
This is illustrated by the fact that concordance rates among identical
twins, even raised in the same household, are surprisingly low. Only Transfused Self-platelet
20% of twins of patients with RA also get RA. There are many platelet
examples of environmental factors causing either chronic or transient
autoimmune diseases. There are postinfectious syndromes such as Fig. 25.4 EPITOPE SPREADING AS A POSSIBLE AUTOIMMUNE
postmycoplasmal cold agglutinin disease. The pattern of incidence MECHANISM FOR POSTTRANSFUSION PURPURA (PTP). Events
b
of multiple sclerosis suggests a viral etiology, although no causative are depicted as progressing from left to right. An HPA-1 person is transfused
a/b
virus has ever been convincingly demonstrated. Another category of with an HPA-1 platelet product. An alloantibody response ensues as an
a
infectious associations includes postviral myocarditis, which follows HPA-1 –specific B cell recognizes the platelet, becomes activated to secrete
a
a
certain coxsackievirus infections. It is sometimes conceptually dif- antibody, and presents the HPA-1 antigen to an anti-HPA-1 T cell (step 1).
ficult to draw a line between viral damage and consequent immune In addition, the activated B cell may now activate a previously ignorant
b
system damage; however, if sensitization to self-antigens occurs as a anti-HPA-1 –specific T cell to initiate an autoimmune response (step 2). The
b
consequence of viral infection and these later are pathogenic targets activated B cell acquired the self-HPA-1 antigen as a passenger on the
a/b
independent of viral antigens, it seems reasonable to consider the HPA-1 allogeneic platelet. This autoreactive T cell can then activate an
b
syndrome as autoimmune. ignorant anti-HPA-1 B cell to make an autoantibody response (step 3) in
Infections are not the only source of environmental stimuli for response to autologous platelets. Note that the sensitization involved in steps
autoimmunity. Toxins, such as mercury, cause autoimmunity in 1 and 2 may take place in a primary response during the first transfusion or
animal models. Another form more familiar to those in hematology exposure and that step 3 may take place in a clinically noticeable way only
is drug-induced autoimmunity, as in AIHA. Drugs such as procain- after a secondary exposure to homologous platelets.
amide that cause lupus-like syndromes are particularly prominent
examples. Despite these specific examples, the environmental factors
that play a role in promoting common autoimmune diseases such as are specific for the foreign HPA-1a antigen and become activated.
RA or SLE are unknown. Moreover, these activated B cells can then present self-platelet
antigens along with costimulatory signals to self-reactive T cells.
Examples in Hematology: Epitope Spreading in When this happens, the immune response can perpetuate even in the
absence of the foreign platelets. This is exactly what is seen in PTP,
Posttransfusion Purpura in which a delayed response continues to eliminate self-platelets for
many days after the disappearance of the transfused platelets. Thus
One potential way to break self-tolerance may be particularly relevant a foreign platelet is analogous to foreign cytochrome c in having a
to syndromes found in hematology and is worthy of elaboration. few different antigens along with many shared antigens. In the same
This is a form of environmental stimulation, albeit iatrogenic. In way as shown experimentally with cytochrome c, it is hypothesized
PTP, transfusion with allogeneic platelets that contain a platelet- that the few foreign antigens existing on the same particle (in the
specific antigen (e.g., HPA-1a) lacking in the recipient leads to rapid case of cytochrome c, it is the same molecule) allow spreading of
destruction of the transfused platelets and antibody formation (in autoimmunity from a foreign antigen to self-antigens. The key events
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this case, anti-HPA-1a antibodies) to the foreign platelet antigen. are the activation of ignorant B cells that cross-react with both self
However, several days later, the recipient becomes severely throm- and foreign molecules and then the activation of T cells that are
bocytopenic owing to a paradoxical destruction of the recipient’s specific for self by these B cells.
own platelets. Although how such destruction of self-platelets occurs It is reasonable to question how such antiself responses are ever
secondary to destruction of allogeneic platelets is controversial, the stopped once started. PTP, for example, is a self-limited syndrome.
best explanation is the development of an autoimmune response. In fact, the answer is not known; however, both downregulation
How does this response get stimulated? The probable pathway of antigen as the platelet count falls to near zero, and the natural
bears significant parallels to one demonstrated in mice a number of mechanisms that cause apoptosis of responding lymphocytes prob-
28
years ago by Janeway and colleagues. These workers immunized ably play a role. Regulatory T cells could also help bring the response
normal mice with human cytochrome c, which differed slightly under control. In the absence of an autoimmune-prone host who has
from endogenous murine cytochrome c. The mice made both an mutations affecting the downregulation of immune responses, these
antibody response and a T-cell response to the human cytochrome c; autoimmune reactions will remain transient. It is speculated that
however, because the human and mouse cytochromes are so similar, when similar events—for example, a response to a viral DNA-binding
the antibody response (but not the T-cell response) cross-reacted protein that eventually spreads to allow for responses to self-DNA
with murine cytochrome c. Presumably this reflected activation and chromatin, as in SLE—occur in people who do have geneti-
of ignorant B cells with specificity for self-cytochrome c (and also cally based problems in downregulating such responses, a chronic
human). However, several weeks later, if the mice were given a dose autoimmune syndrome can be induced.
of self-cytochrome c, now both a vigorous B-cell and T-cell antiself
response ensued. These authors suggested that priming with the
cross-reactive antigen first induced self-reactive B cells, which in IMPLICATIONS AND THERAPY
turn could then break tolerance in anergic or ignorant self-reactive
T cells. The significance of this issue to hematology ranges from syndromes
How does this relate to PTP? Fig. 25.4 illustrates the author’s such as AIHA and ITP to iatrogenically induced autoimmunity as
hypothetic adaptation of this mechanism to the platelet transfu- in PTP. A basic understanding of the mechanisms of self-tolerance
sion situation. The foreign platelets actually share many common and their breakdown in autoimmune disease raises the possibility
antigens with the host, as well as differ at the HPA-1a locus. The of many types of specific therapeutic interventions. One of the
foreign antigenic difference allows ignorant self-specific B cells (as clearest would be to identify initiating factors, such as infections,
well as HPA-1a–specific B cells) to interact with helper T cells that and to prevent or treat them. A second approach would be to reset