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Chapter 25 Tolerance and Autoimmunity 289

role in systemic autoimmunity for Toll-like receptors (TLRs), which T cell with specificity for the same self-antigen simply does not exist.
recognize molecules specific to pathogens and induce costimula- Thus the generation of B cells expressing antiself antibodies in the
tory molecules and immune system activation. Ligands for TLRs germinal center is largely avoided by the lack of T-cell help for the
include lipopolysaccharide (TLR4), bacterial DNA enriched for self-antigen.
CpG dinucleotides (TLR9), and single-stranded and double-stranded
RNA (TLR7 and TLR3). TLRs can be activated by infection and
may provide a mechanism by which some infections can trigger Control of Self-Reactive Lymphocytes: Downregulation
autoimmunity. However, in the right context some self (as opposed
to pathogen) molecules, such as DNA found in chromatin, a target The difference between transient autoimmune responses and chronic
for systemic lupus erythematosus (SLE) autoantibodies, can also severe autoimmunity may lie in the third layer of protection against
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activate TLRs (TLR9 in the case of DNA). Third, certain “pro- autoimmunity: downregulation of ongoing responses. Again, this layer
fessional” APCs, such as dendritic cells, may constitutively express is a normal part of the immune system, functioning to regulate both
these costimulatory molecules at moderate levels and can start the normal and autoimmune responses. Initially, in a normal response
cascade, for example, by activating T cells, which is then amplified to a viral pathogen, there is clonal expansion of lymphocytes specific
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by T–B interactions. In summary, there are two main functions of for viral antigens. This process leads ultimately to the elimination of
costimulatory requirements: (1) they focus the interactions between the pathogen, which was traditionally thought of as the signal to stop
two antigen-specific T and B cells and limit nonspecific interactions, an immune response. However, when the pathogen is eliminated, in
and (2) they restrict immune responses in the absence of inflam- the absence of any other regulatory mechanism, there would be many
mation. Both of these features of costimulation tend to prevent residual cells that had been responding to the pathogen. Although a
the activation of self-reactive lymphocytes that exist in peripheral few such cells could be retained to provide immunologic memory,
lymphoid organs. For B cells, this means that tolerance in the T-cell most of these are no longer useful in the short term. In addition to
compartment alone will prevent many self-reactive B cells from being unnecessarily filling the lymphoid compartment, these cells may be
activated. a risk for causing autoimmunity. For example, there is a possibility
Even with antigen sequestration and costimulatory regulation, that lingering B cells will contribute to the generation of newly
mechanisms that prevent the activation of self-reactive lymphocytes autoreactive B cells by virtue of random somatic hypermutation.
are incomplete at best. For example, it seems likely during infection Thus elimination of most of the reactive B cells regardless of specific-
or trauma that antiself responses could initiate because costimula- ity would mitigate this problem.
tory molecules will be nonspecifically induced. Furthermore, during Several pathways for the removal of such postexpansion cells have
infection and tissue damage, self-proteins that ordinarily are seques- been elucidated. One seems to be an inborn program that causes cells to
tered can be released. This leads to activation of the ignorant cells undergo apoptosis after a certain amount of proliferation. Particularly
circulating in the body. In fact, (usually) self-limited autoimmune important in this program in lymphocytes are the Bcl2-inhibitable
responses after infection are well known, such as poststreptococcal pathways that are activated in large part by the pro-apotoic protein
glomerulonephritis or postmycoplasmal cold agglutinins. Although Bim. In B cells, CD40 signaling in concert with BCR stimulation and
these syndromes can cause serious clinical problems, they are self- cytokines (IL-4 and IL-21 provided by Tfh cells) rescue these cells
limited, unlike autoimmune diseases such as SLE. from this self-destructive fate, allowing these cells to become long-lived
memory cells or plasma cells. There are also active mechanisms such
as Fas and FasL that signal cells to apoptose. Generally, when Fas is
Tolerance of Germinal Center B Cells ligated by FasL, the cell expressing Fas is triggered to die by apoptosis.
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Fas and FasL are not expressed at high levels on unstimulated resting
Fig. 25.1 indicates that there are yet other stages of B-cell develop- lymphocytes. On activation, T cells express both Fas and FasL,
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ment at which one could imagine that self-tolerance should occur. whereas B cells express Fas. Thus, after a certain degree of activation
The most important of these is during the germinal center reaction. and proliferation, a T cell (expressing FasL) encountering an activated
After initial activation and expansion of antigen-activated B cells, the B cell (expressing Fas) may actually kill that B cell. There are likely
genes that encode the antibody receptor molecule undergo a process other ligand pairs, particularly those in the tumor necrosis factor
of random mutation. This process known as somatic hypermutation or (TNF) family that may serve similar functions, both for B and T cells.
affinity maturation allows editing of the template antibody molecule Another method of downregulating immune function is the
in an attempt to increase affinity of the antibody against the immu- acquisition of inhibitory receptors. For example, CTLA4 is an inhibi-
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nizing antigen. The B cells that have mutated their antibodies then tory receptor expressed on activated T cells, and when ligated by
compete for the same antigen in the germinal center for selection of CD80 or CD86, causes inactivation of the receptive T cell. CD80
B cells expressing higher affinity antibodies. However, a side effect of and CD86 send a positive signal to naive T cells by ligating CD28;
any random process, just as in the receptor rearrangement itself, is the however, CTLA4 has higher affinity for CD80/86 allowing it to
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potential to create novel antiself specificities. This problem is dealt outcompete binding of CD80/86 to CD28. Thus the same ligand can
with because T and B cells are dependent on each other for activation. promote activation early on in the immune response while, through a
Germinal centers contain a recently characterized specialized T-cell change in the receptive T cell, it can inhibit activation at a later time.
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subset known as T follicular helper cells (Tfh). For germinal center An analogous receptor pair of the B7 family is PD-1, an inhibitory
B cells to survive, they must incorporate an antigen through its BCR, receptor similar to CTLA-4, and its ligands PD-L1 and PD-L2. PD-1
then process and present the antigen on MHC class II molecules. is expressed on a number of activated lymphocytes and its ligands are
Only B cells that have incorporated the relevant antigen and can constitutively and inducibly expressed on a variety of parenchymal
interact with antigen-specific Tfh cells are allowed to survive and cells and hematopoietic cells. Absence of these molecules leads to
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differentiate into memory B cells or plasma cells. It is evident that exaggerated immune responses and autoimmunity. These examples
for this to occur, B and Tfh cells specific for the same self-antigen underscore the careful means by which the immune system regulates
must be in the same place at the same time. If such cells are rare, and dampens activation presumably to prevent excessive immune
then the requisite coexistence of two such cells will happen very responses and autoimmunity.
infrequently, minimizing the chance of starting an autoimmune reac-
tion. A second consequence of T–B interdependence is that specific
inefficiencies of central tolerance in one limb can be compensated Control of Self-Reactive Lymphocytes: Channeling the
for in the other. For example, T cells are probably very efficiently Type of Effector Response
purged of cells that react with thymus-specific antigens, but B cells are
probably not. However, antithymus B-cell responses are unlikely even A final layer of protection against self-inflicted immune damage
though many thymus-specific B cells probably circulate; the cognate involves channeling of responses so that they are less harmful.