Page 230 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 14 The Microbiota in Immunity and Inflammation 209

KeY COnCePtS acquires antibodies of the IgG isotype both in utero and via the
Definitions breast milk. These antibodies serve to limit enteric infection in
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the newborn and dampen neonatal mucosal T-cell and germinal
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• Microbiota: A collective term for all the microscopic organisms that center (GC) B-cell responses to commensal antigens. Maternally
reside on or in the human body. acquired anticommensal antibodies can transfer bound microbial
• Microbiome: The combined genomes of all the organisms that molecules to the offspring during gestation and via the breast
constitute the microbiota. milk. This transfer of microbial products contributes to the
• Mycobiota: That subset of the microbiota that includes fungi alone. earliest education of the immune system and limits deleterious
• Virome: the collection of all viruses, including viruses integrated into postnatal inflammatory responses. Breast milk is also a rich
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the human genome, found in or on humans.
• Dysbiosis: A condition in which there is disequilibrium of the microbial source of immunosuppressive transforming growth factor-β
communities that constitute the microbiota at a given body site. (TGF-β) and interleukin-10 (IL-10) (Chapter 9), which also help
• Germ-free: Experimental animals birthed and raised in a sterile environ- promote tolerogenic responses to the microbiota. 9,10
ment, devoid of microbes.
• Gnotobiotic (“known life”): Describes animals in which the full MICROBIOTA-DEPENDENT MATURATION OF THE
complement of colonizing microbes is known.
INTESTINAL IMMUNE SYSTEM
Microbial colonization prompts a rapid organization of immune
structures that are quickly seeded with immune cells. This process
Prenatal Development of the Immune System helps avoid overexuberant responses to the microbiota and sets the
In the fetal liver, some common lymphoid progenitor cells— stage for continued tolerance of commensals and for defense against
ancestral to all lymphocytes—develop into a specialized subset pathogens in the future. The intestinal epithelium limits direct
of innate lymphoid cells (ILCs) referred to as lymphoid tissue encounter between luminal microbes and the immune cells in the
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inducer (LTi) cells. As their name implies, LTi cells are essential underlying lamina propria not only by forming a physical barrier
for the development of all secondary lymphoid structures but also by the production and/or transport of immune and
throughout the body. These structures will eventually become antimicrobial factors (Fig. 14.4). Thus the epithelium is an essential
the sites for initiation of immune responses to the commensal component of the elaborate network of checks and balances that
microbiota, pathogenic invaders, and self antigens. In the develop- synergize to help to keep pathogens at bay while limiting or prevent-
ing fetus, LTi cells promote the development of mesenteric lymph ing collateral damage induced by pathogens and commensals.
node (MLN) and of the Peyer patches (PPs) (Chapters 2 and
20) in the distal ileum (Fig. 14.3). They also recruit B and T Gut-Associated Lymphoid Tissues
lymphocytes to these tissues and facilitate their organization Although MLN and Peyer patches begin to develop before birth,
into distinct B-cell follicles and T-cell zones, respectively. complete maturation does not occur until after birth. Germ-free
Throughout life, the MLN provides a so-called mucosal firewall or “germ-reduced” mice display reduced size and cellularity and
that prevents systemic dissemination of gut bacteria. altered numbers and distribution of immune cells both in the
Other local mechanisms are also initiated to limit host collateral gut and gut-associated lymphoid tissues (GALTs). Thus maturation
damage to the neonatal intestine by early microbial encroachment. of the mucosal immune system is contingent on the acquisition
For example, Toll-like receptor 4 (TLR4), the receptor for of microbiota. A third type of secondary lymphoid tissue—isolated
lipopolysaccharide (LPS) that is derived from gram-negative lymphoid follicles (ILFs), which are also induced by LTi cells—is
bacteria, is highly expressed by intestinal epithelial cells (IECs) also completely dependent on colonization with the microbiota
prior to birth, but its expression and signaling are rapidly and thus only develops postnatally.
downregulated following onset of colonization. In addition, a LTi cells cluster at the base of the crypts in structures referred
diverse array of lymphocytes collectively referred to as intraepi- to as cryptopatches. Stimulation of cryptopatches by peptidoglycan
thelial lymphocytes (IELs) can be found intercalated between derived from gram-negative bacteria induces recruitment of B
the IECs. IELs display multiple features of activated cells and cells, thereby forming ILFs. The importance of ILFs in the direct
participate in the maintenance of epithelial barrier integrity by control of bacterial growth is demonstrated by the fact that mice
limiting bacterial translocation and promoting epithelial repair devoid of mature ILFs display an overrepresentation of gram-
following injury. 5 negative bacteria. 11
Passive Acquisition of Antimicrobial Immunity Innate Lymphoid Cells
The microbiota of the neonate is acquired from his or her mother, ILCs represent an early line of defense at mucosal surfaces. ILCs
who has already established tolerogenic relationship with the are classified as LTi or “LTi-like” (described above) cells or as
same microbiota. The mother’s “mucosal memory” also gets “helper-like” cells. The progenitor of helper-like ILCs is distinct
transmitted to her offspring. During transvaginal delivery, this from that of LTi cells or natural killer (NK) cells. “Helper-like”
mucosal memory is seeded with the mother’s native microbiota. ILCs are classified into three main subcategories based on their
Mothers produce antibodies to bacteria-derived antigens. These expression of particular sets of surface receptors, transcription
bacteria-responsive antibodies enter the maternal circulation factors, and secreted proteins. Unlike their adaptive, thymus-
and ultimately get passed to the offspring in breast milk. Immu- derived counterparts, ILCs do not express antigen receptors and
noglobulin A (IgA) is the major antibody isotype generated by are therefore activated by cytokine signals. This enables ILCs to
mammary glands (Chapter 15). IgA inhibits bacterial translocation launch an initial rapid response to microbial challenge and
across the neonatal intestinal epithelium, thereby limiting col- facilitate the development of an adaptive lymphocyte-mediated
lateral damage by an encroaching microbiota and providing immune response. ILC1s, such as T-helper type 1 (Th1) cells,
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passive immunity to pathogenic infection. The offspring also express the transcription factor Tbet and secrete interferon-γ