By Q. Vatras. Loyola University, Chicago.
Perhaps the notion that sarcopenia is due to a simple exhaustion of the satellite cell pool or reservoir is overly simplistic generic ampicillin 500 mg without prescription. Notwithstanding purchase 250 mg ampicillin with visa, sarcopenia must be an important component of change in the bone-muscle interface buy cheap ampicillin 250mg on-line. Polar moment of inertia and cortical thickness were markedly increased suggesting a role for this neurotropic factor on the periosteum as well as the trabecular and cortical skeleton purchase ampicillin in india. The effects of the sympathetic nervous system on bone have recently been explored and may be important during aging since several investigators have sug- gested there is an increase in sympathetic tone with advanced age . Beta adren- ergic activation of receptors on the osteoblast causes uncoupled bone remodeling such that formation is suppressed and resorption is increased within the bone mar- row milieu and trabecular skeleton. The effects of adrenergic activity on the perios- teum are not known, although nerve bers are present in this highly vascular environment. Cortical thickness was markedly reduced at 72 weeks vs wild type age-matched controls, as was trabecular bone volume . Interestingly, periosteal expansion with aging did not occur in these mice leading to a much thinner bone during aging with enhanced skeletal fragility. Whether sympathetic tone prevents periosteal expansion as a compensatory mechanism during mammalian aging requires further investigation. Aging and the Bone-Muscle Interface 271 9 Research Directions: Musculoskeletal Aging as a Determinant of Healthspan Aging is a physiologic process that affects the entire organism, including the mus- culoskeletal system, through the pillars related to healthspan. There is the direct impairment in bone formation and the acceleration in resorption that occurs over time in virtually all mammals primarily as a result of changes in the stem cell pool, as well as chronic inammation, and greater accumulation of reactive oxygen spe- cies. There is a secondary increase in periosteal formation in response to bone loss albeit not to the degree that matches an increase in medullary expansion. There are also indirect cell non-autonomous effects in the aging animal including enhanced sympathetic tone, changes in the parathyroid/vitamin D axis, impaired renal func- tion, and gonadal deciency. Coincident with the aging skeleton, muscle mass is also declining and its function is reduced. As discussed above, the bone-muscle interface plays a critical role in modulating skeletal loading as well as cell signaling. Future research should start by more fully delineating how each of the pillars that compose the aging process affect bone, muscle and the interface between the two. One major thrust should be in dening how the periosteum could be resistant to several of the determinants that impair healthy aging and its relationship to sarcope- nia. Although the periosteal envelope can expand with aging, it is unclear whether the signals for that arise from the muscle, the bone matrix, from other bone cells or from an enhanced sensitivity to loading. One limitation is that studies of the perios- teum have been relatively limited due to the difculty in isolating the progenitor cells and studying them ex vivo. Even if models were developed to study the bone- muscle interface, we still do not know whether its expansion has any impact on muscle function. On the other hand, we know that by increasing periosteal surface tension, biomechanical properties improve or at least stabilize in the face of endos- teal resorption. In that same vein, delineating the communication network between osteocytes (mechanical sensors) and the periosteum will be essential for dening age-related periosteal effects. A more important question is whether the periosteum is protected from several critical determinants that dene aging; i. A focus on the Foxo proteins during aging provides the rst clues as to some of the protective mechanisms inherent within the cell that may be operative during aging. Another important aspect of the bone muscle interface lies in the remarkable gender differences in the periosteal envelope across all ages. This parallels the dif- ferences in muscle mass and bone size that is observed between males and females, suggesting that there is always a factor based on size that determines the musculo- skeletal mass. But it is not clear whether periosteal osteoblasts differ between males and females, and if aging has a selective effect (positive or negative) on the ability of these bone-forming cells to expand and lay down collagen. Rosen Sarcopenia is a huge clinical problem because of the falls that result from muscle weakness. It is uncertain how progressive but modest muscle loss directly affects the skeleton and in particular the periosteum. Targeted therapy with myokine ago- nists or antagonists are soon to be developed for frailty, yet we know little about the mechanisms at the bone-muscle interface. Understanding the role of neuropeptides at the bone-muscle interface provides another targeted area for research, particularly with aging. Remarkably, Cthrc1 is highly expressed in the pituitary and hypothalamus and circulates in mea- sureable quantities. The new discipline of Geroscience attempts to merge the physiology of aging with an understanding of the pathophysiology of age-related diseases and the delin- eation of the pillars that dene age-associated disorders. We can no longer afford to study major organ systems in isolation with age, and a major thrust for future stud- ies will be in dening regulation of the bone-muscle interface and the downstream consequences that result from impairment in either tissue. Reeve J, Loveridge N (2014) The fragile elderly hip: mechanisms associated with age-related loss of strength and toughness. Seeman E (2013) Age- and menopause-related bone loss compromise cortical and trabecular microstructure. Ferretti C, Mattioli-Belmonte M (2014) Periosteum derived stem cells for regenerative medi- cine proposals: boosting current knowledge. Vokes 1 Clinical Aspects of Osteoporosis Osteoporosis is a generalized skeletal disorder in which decrease in bone mass and deterioration of bone quality lead to bone fragility and increased risk of fracture. Osteoporosis is primarily a disease of the elderly, with more than 70 % of fractures being sustained by those 65 or older . Fragility fractures, also termed osteoporotic fractures or low trauma fractures, occur when falling from a standing height during usual physical activity . Fractures result from an interaction between bone strength and the mechanical force applied to it, usually during a fall. Younger individuals may experience fragility fractures when they have diseases or take medications that have harmful effects on bone. However, bone strength is inuenced by bone quantity (mass) and bone quality, both of which decrease with age, thus leading to an increase in fragility fractures among the elderly. In addition, elders have an increased risk for falls, which further contributes to increased fracture incidence. Because the risk of osteoporotic fractures increases with age , this population growth will likely result in increased numbers of fractures and associated health care costs. Osteoporotic fractures result in signicant morbidity, mortality, and reduced quality of life . Hip fractures are associated with increased mortality, loss of independent living, and decline in functional status [4 6]. Osteoporotic fractures accounted for nearly 50 % of hospitalizations among women 75 years and older. Although the hospitalization rates for all other diseases declined during this 11 year observation period, the rate of hospitalization for non-hip fractures actually increased [11 ]. From  Hip Radiographic vertebral Wrist 300 200 100 0 400 Women 300 200 100 0 Age(years) 280 J. Fracture risk increases with age in all populations studied  and women have approxi- mately twice as many fractures as men although female-to-male ratios vary depend- ing on the skeletal site of fracture and the geographic region (Fig. There are signicant geographic, racial, and ethnic differences in fracture rates, the reasons for which have not been clearly identied. Although some of these differences may be due to under-reporting of fractures in countries with less developed medical care, there are probably true differences in fracture risk that are due to genetic as well as environmental factors. The best-studied geographic differences are for hip fracture rates because those fractures are most likely to be reported accurately (Fig. Age- standardized rates of hip fractures reported from over 60 countries around the world vary by over 200-fold in women and 140-fold in men . Even within the same continent there are sig- nicant differences between countries. Similarly, in the Middle East, the rates of hip fracture are 8 times higher in Iran than in Tunisia (Fig. In contrast to hip fractures, vertebral fractures do not show as much geographic variability. This is particularly true for morphometric (radiographic) vertebral frac- tures, which have similar prevalence in studies from different regions of the world [12 14]. It is likely that genetic differences account for at least some of the observed disparity. Finally, regional differences in fall risk have been reported and may contribute to differences in fracture rates [15, 16 ]. The most peculiar observation regarding geographic differences in fracture rates is a recent nding of hip fracture rates increasing in the east (China) while decreas- ing in the west (Western Europe, North America, and Oceania) .
Iron The idea that body iron stores ampicillin 500mg low cost, usually measured as serum ferritin buy ampicillin cheap, are important in hair growth is controversial and as yet unsubstantiated in a randomized controlled clinical trial (70) cheap ampicillin 500 mg amex. In an open trial of cyclical treatment with cyproterone acetate in women with serum ferritin levels above and below 40 g/l (10 subjects in each group) hair densities increased by about 15% in the high ferritin group after one year of treatment but were unchanged in the low ferritin group (71) purchase 250mg ampicillin amex. However, there are no peer-reviewed trials that have tested the effect of iron supplementation on hair growth. Unfortunately, such trials are expensive and unlikely to be supported by the pharmaceutical industry in view of the lack of commercial potential. In the absence of more conclusive data it seems reasonable to check the serum ferritin and advise dietary supplementation with iron in those with a level below 40 g/L. Patients should be advised that iron treatment alone will not halt or reverse hair loss but it may improve the response to specic treatments. Treatment of Non-Caucasians The principles of managing androgenetic alopecia in non-Caucasians are generally the same as in Caucasians although there is relatively little published trial data. A large controlled study from Japan found that nasteride 1mg stimulated hair growth in nearly 60% of men with androgenetic alopecia (i. Improvement in hair growth in these men was almost as good as in those taking the higher dose (72). In a controlled trial of 1% minoxdil solution in the treatment of 280 Japanese women with androgenetic alopecia 29. Issues around the management of androgenetic alopecia in African women, including detailed consideration of surgical treatment, are discussed in a recent review (74). Topical minoxidil remains the mainstay of treatment in this group but patients should be warned that 116 Messenger the use of a solution-based product can return straightened hair to its natural curly state. In the author s experience minoxidil solution is more likely to cause hypertrichosis in women from the Indian subcontinent and the Middle East than in Europeans, particularly in the fronto-temporal and sideburn regions. For many patients this is an acceptable side effect but they should be advised about it before starting treatment. The emo- tional aspect of hair loss means that it is not necessarily a trivial issue for the sufferer and, conse- quently, managing the patient with androgenetic alopecia can be difcult and time-consuming for the physician (the same is true of other hair loss disorders). Nevertheless, it can be rewarding to manage patients with androgenetic alopecia and, despite their limitations, current treatments can be of signicant benet providing the patient is fully aware of what can be achieved. Our knowledge of hair biology is expanding rapidly and we are making progress in understanding the genetic and molecular basis of androgenetic alopecia. It is unlikely, however, that medical treatments to reverse follicular miniaturization will be forthcom- ing in the foreseeable future and perhaps the best prospect for a more effective treatment will come from the clinical application of hair-follicle cell culture methods (76). The other approach is for there to be a sea change in cultural and societal attitudes toward hair loss. This may seem a bizarre and unlikely prospect but one that is not beyond the bounds of possibility if a few more celebri- ties could be persuaded to aunt their hair loss rather than advertise ctitious remedies. Classication of the types of androgenetic alopecia (common baldness) occurring in the female sex. Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of nasteride 1 mg treatment of men and postmenopausal women. Follicular miniaturization in female pattern hair loss: clinicopathological correlations. Characterization of inammatory inltrates in male pattern alopecia: implications for pathogenesis. Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue. The effects of N,N-diethyl-4-methyl-3- oxo-4-aza-5androstane-17carboxamide, a 5reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque. Hair growth effects of oral administration of nasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. Role of androgens in female-pattern androgenetic alopecia, either alone or associated with other symptoms of hyperandrogenism. Serum androgens and genetic linkage analysis in early onset androgenetic alopecia. Insulin gene polymorphism and premature male pattern baldness in the general population. Polymorphism of the androgen receptor gene is associated with male pattern baldness. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. The E211 G>A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia. The psychosocial consequences of androgenetic alopecia: a review of the research literature. Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. Psychological characteristics of women with androgenetic alopecia: a controlled study. The reliability of horizontally sectioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and2% topical minoxidil, placebo or no treatment. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil. The effects of nasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Use of nasteride in the treatment of men with androgenetic alopecia (male pattern hair loss). An open, randomized, comparative study of oral nasteride and 5% topical minoxidil in male androgenetic alopecia. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus nasteride. Quantitative assessment of spironolactone treatment in women with diffuse androgen-dependent alopecia. The diagnosis and treatment of iron deciency and its potential relationship to hair loss. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl oestradiol treatment of diffuse androgen-dependent alopecia in women. A randomized, placebo-controlled trial of 1% topical minoxidil solution in the treatment of androgenetic alopecia in Japanese women. Patients present with a complaint of increased shedding over normal levels and associated diffuse alopecia. The excessive shedding is the result of alterations of the hair-growth cycle with premature conversion of anagen follicles to telogen follicles, which represents a shift of 7 25% of anagen follicles to telogen (Fig. It presents as acute (<4 months), chronic (>4 months), and chronic-repetitive (Fig. The primary insult is to the dermal papillae of the anagen fol- licle, which induces an early shunt to telogen. Regeneration of the follicle is determined by the bulge area, so any damage, stress, or inammation that involves the bulge will affect regenera- tion (Fig. The shedding results in a diffuse loss with a more prominent central and frontal scalp loss. The patient usually relates loss of body hair and a diminished rate of hair growth, espe- cially of leg hair. When a trigger is identied and removed or treated, the patient experiences diminished shedding and later regrowth of hair (Table 3). The differential diagnosis of diffuse alopecia includes androgenetic alopecia, diffuse alopecia areata, and an inammatory alopecia such as central centrifugal cicatricial alopecia and lichen planopilaris, especially when the primary loss involves the central scalp. A light hair pull will extract loose hair, which can be then examined under 2x magnica- tion. If there are numerous dystrophic anagen hairs, the diagnosis is an anagen efuvium. Anagen efuviums are the result of severe insult to the dermal papillae, which produces 80% loss of scalp hair.
Further sampling may eventually nd that the Ugandan isolates are part of a wider population in which some recombination occurs discount ampicillin express. The protozoan Plasmodium falciparum has an obligate sexual phase that occurs during transmission in the mosquito vector purchase ampicillin 250 mg online. In geographic regions where infection is common discount 500 mg ampicillin visa, the vector frequently picks up mul- tiple genotypes discount ampicillin 500 mg free shipping, which then mate andrecombinebefore transmission to a new host. By contrast, regions with sparsely infected hosts have alowerprobability of mixed genotypes in the vectors, leading to fre- quent self-fertilization and limited opportunity for recombination be- tween lineages (Babiker and Walliker 1997; Paul and Day 1998; Conway et al. Within areas of low infection intensity, they found strong linkage disequilibrium, low genetic diversity, and high variation between geographic locations. This provides another exam- ple in which the genetic structure varies across space. The segments act like distinct chromosomes but do not pair and segregate as in eukaryotic cells. Instead, new viral particles form by a sampling process that chooses approximately one segment of each type. However, reas- sorting segments are easier to study because the segments mark dis- cretely and clearly the units of recombination. It appears thatrarereassortments have occasionally introduced hem- agglutinin or neuraminidase from bird inuenza into the genome of hu- man inuenza (Webster et al. The novel antigens cross-reacted very little with those circulating in humans, allowing the new combina- tion to sweep through human populations and cause pandemics. Lack of reassortment maintains discrete strains with strong linkage disequilibrium between segments. This is another way of saying that, after reassortment, discrete lineages accumulate new mutations on dif- ferent segments and keep those new mutations together within the lin- eage, creating linkage disequilibrium. Common reassortment reduces linkage disequilibrium between seg- ments by bringing together genetic variants that arose in dierent indi- viduals. Reassortment causes dierences in the phylogenetic history of dierent segments within a virus. Reassortment may be common between viruses within a population, but that population may not mix with viruses from another population. But isolated populations do not share the same associations between genetic variants and thus exhibit linkage disequi- librium relative to each other. Equivalently, the segments within each isolated population have a common phylogeny that diers relative to the phylogenetic history of the segments in other populations. No studies have sampled over dierent spatial and temporal scales or studied the processes that cause barriers to reassortment. The best studies I found examined the phylogenetic histories of the various seg- ments of inuenza. Several papers describe reassortment between segments of inuenza C(Buonagurio et al. By contrast, phylogenies of the other six segments identify three or four distinct lineages, in which each lineage contains older isolates as well as recent isolates. The phylogenetic patterns for seven of the eight inuenza B segments show clear patterns of reassortment (Lindstrom et al. Concordant phylogenetic patterns between segments suggest cotransmission of those segments. However, the sample size is small, and the observed concordances may simply be the chance outcome from a small number of reassortment events. The columns show the seg- ment type for each of eighteen isolates, with each segment separated into two types and assigned primary anity for either the Yamagata-like or Victoria-like strains. The appearance of Victoria-like segments in some Yamagata-like isolates demonstrates reassortment, as does the appearance of Yamagata-like segments in some Victoria-like isolates. Those internal genes did not accumulate changes sequentially over time in a single lineage. For example, the basic polymerase-1 protein, the nucleoprotein, and the matrix protein isolated in 1997 were phylogenetically closer to isolates from 1993 1994 than to isolates from 1995. This study shows linkage of the antigenic determinants but reassort- ment of other genetic components. Several cases of recombination have been described (summa- rized by Worobey and Holmes 1999), for example, between vaccine and wild-type polio strains (Guillot et al. Recombinants may strongly aect evolutionary patterns even when the frequency of recombination per generation is very low. Occasional recombinants can create the mosaic progenitors of successful lineages (Worobey and Holmes 1999). In addition, recombination means that a particular virus does not have a single phylogenetic history instead, each part of the genome may tracebacktoadierent ancestral lineage. Recombination can occur only when host cells are coinfected by dif- ferent viral genotypes. Preliminary reports suggest that some viruses can recombine frequently when genetic variants coinfect a cell (Martin and Weber 1997; Fujita et al. Many viruses may be similar to the Plasmodium example cited above, in which the frequency of multiple in- fection by dierentgenotypes determines the degree of genetic mixing between lineages. The frequency of recombination between genetic variants undoubt- edly varies among viruses. Recombination is suciently frequent that a small subset of the genome provides a poor indicator of the phylogenetic history for the entire genome. Thus, strain typing may have little meaning because highly diverged variants merge by recombination into a single gene pool. By con- trast, rare recombination leaves most lineages identiably intact as dis- crete strains. With discrete strains,occasional recombinant mosaics can be identied as the mixture of known strains. Most isolates appear to have a phylogenetic anity for a particular clade, but multiple recombination events and genomic mo- saics also occur frequently (Bobkov et al. The opposing aspects of discrete strains and widespread recombination probably reect heterogeneous histories in dierent locations, the temporal and spatial scales of sampling, and the rapidly changing nature of the viral populations as the infection contin- ues to spread. Analysis of the gag genomic regions and longer sequences in the env region showed a high frequency of recombination within this population. Overall, the Democratic Republic of Congo population had all known subtypes, a high degree of diversity within eachsubtype,andsignicant mosaicism across dierent genomic regions. This suggests a relatively old and large population that has accumulated diversity and probably been the source for many lineages that have colonized dierent parts of theworld (Vidal et al. Subtype Aisrelatively common in the eastern African countries around the Ivory Coast, and subtype C dominates southern Africa. Each region may accumulate signicant diversitywithinitsdominant subtype, with frequent recombination between subtype variants. Recombination between subtypes then mixes the distinct phylogenetic histories of the subtypes. Such re- combinations probably have become increasingly common, for example, the admixtures of subtypes occurring along the routes of intravenous drug user transmissions in China (Piyasirisilp et al. Drug users in Greece and Cyprus also appear to be fertile sources of recombinants between subtypes (Gao et al. Such recombination between antigenic sites can strongly inuence the evolutionary dynamics of antigenic variation because new genotypes can be generated by combinations of existing variants rather than waiting for rare combinations of new mutations. Those studies dened strains mainly by measurement of genetic variability at nonanti- genic loci (Enright and Spratt 1999). In this section, I focus on genetic variability between lineages when dened by dierences at antigenic loci. Immune pressure by hosts can potentially separate the parasite population into discrete, nonoverlap- ping antigenic types (Gupta et al. Suppose that a haploid parasite with alleles at two dierent loci, A/B,infectsmany hosts during an epidemic, leaving most hosts recovered and immune to any parasite genotype with either A or B. Thus, host immunity favors strong linkage disequilibrium in the parasites, dominated by the two nonover- lapping genotypes A/B and A /B.
Any particular bacterial cell typ- ically expresses only one or two of the opa loci; cellular lineages change expression in the opa loci (Stern et al purchase ampicillin 250 mg otc. The bacteria expose the hy- pervariable regions on the cell surface (Malorny et al buy ampicillin with a visa. The exposed regions contain domains that aect binding to host cells and to antibody epitopes order online ampicillin. The dierent antigenic variants within the Opa of proteins family af- fect tropism for particular classes of host cells (Gray-Owen et al order ampicillin 250mg mastercard. This virus links its surface protein gp120 to two host-cell receptors before it enters the cell (O Brien and Dean 1997). These examples show that variable surface antigens may sometimes occur because they provide alternative cell or tissue tropisms rather than, or in addition to, escape from immune recognition. Thisphenomenon is called original antigenic sin be- cause the host tends to restimulate antibodies against the rst antigen encountered. In some cases, antibodies from a rst infection appear to enhance the success of infection by later, cross-reacting strains (see references in Ferguson et al. The mechanisms are not clear for many of these cases, but the potential consequences are important. If cross-reactive strains interfere with each other ssuccess, then populations of para- sites tend to become organized into nonoverlapping antigenic variants that dene strains (Gupta et al. By contrast, if similar epitopes enhance each other s success, then well-dened strain clustering is less likely (Ferguson et al. Simultaneous infection by two related epitopes sometimes interferes with binding by cytotoxic T cells. In natural infections, hosts har- bored both cp26 and cp29 variants more often than expected if epitopes were distributed randomly between hosts. The rst section of this chapter de- scribed how antigenic variation potentially extends the length of infec- tion within a single host. Longer infections probably increase the trans- mission of the parasites to new hosts,increasingthetness of the par- asites. Other attributes of infection dynamics may also contribute to transmission and tness. For example, the density of parasites in the host may aect the numbers of parasites transmitted by vectors. If so, then a good measure of tness may be the number of parasites in the host summed over the total length of infection. It would be interesting to study experimentally the relations between infection length, parasite abundance, and transmission success. Re- ports of original antigenic sin and altered peptide ligand antagonism have come from observations of antigenic variants generated by muta- tion. It would be interesting to learn whether parasites with archival variants also induce these phenomena. One might, for example, nd that some variants induce a memory response that interferes with the host s ability to generate a specic response to other variants. Thus, the antigenic repertoire in archival libraries may be shaped both by the tendency to avoid cross-reaction and by the degree to which variants can interfere with the immune response to other variants. Specicity measures the degree to which the im- mune system dierentiates between dierent antigens. Cross-reactivity measures the extent to which dierent antigens appear similar to the immune system. The molecular determinants of specicity and cross- reactivity dene the nature of antigenic variation and the selective pro- cesses that shape the distribution of variants in populations. The surfaces of par- asite molecules contain many overlapping antibody-binding sites (epi- topes). An antibody bound to an epitope covers about 15 amino acids on the surface of a parasite molecule. However, only about 5 of the par- asite s amino acids contribute to the binding energy. A change in any of those 5 key amino acids can greatlyreducethe strength of antibody binding. The second section focuses on the paratope, the part of the antibody molecule that binds to an epitope. Antibodies have a variable region of about 50 amino acids that contains many overlapping paratopes. Each paratope has about 15 amino acids, of which about 5 contribute most of the binding energy for epitopes. Paratopes and epitopes dene comple- mentary regions of shape and charge rather than particular amino acid compositions. A single paratope can bind to unrelated epitopes, and a single epitope can bind to unrelated paratopes. The third section introduces the dierent stages in the maturation of antibody specicity. Naive B cells make IgM antibodies that typic- ally bind with low anity to epitopes. A particular epitope stimulates division of B cells with relatively higher-anity IgM antibodies for the epitope. As the stimulated B cell clones divide rapidly, they also mu- tate their antibody-binding regions at a high rate. Mutant lineages that bind with higher anity to the target antigen divide more rapidly and outcompete weaker-binding lineages. This mutation and selection pro- duces high-anity antibodies,typically of type IgA or IgG. Natural antibodies from dierent B cell lineages form adiverseset thatbindswithlowanity to almost any antigen. By contrast, in vivo inoculations with several dierent patho- gens showed that the initial binding by natural antibodies lowered the concentrations of pathogens early in infection by one or two orders of magnitude. Poor binding condi- tions cause low-anity binding to be highly specic because detectable bonds form only between the strongest complementary partners. By contrast, favorable binding conditions cause low-anity binding to de- velop a relatively broad set of complementary partners, causing rela- tively low specicity. Early stimulation of B cells appears to depend on the equilibrium binding anity for antigens. By contrast, competition between B cell clones for producing anity-matured anti- bodies appears to depend on the dynamic rates of association between Bcellreceptors and antigens. The sixth section compares the cross-reactivity of an in vivo, poly- clonal immune response with the cross-reactivity of a puried, mono- clonal antibody. Polyclonal immune responses raise antibodies against many epitopes on the surface of an antigen. Cross-reactivity declines lin- early with the number of amino acid substitutions between variant anti- gens because each exposed amino acidcontributes only a small amount to the total binding between all antibodies and all epitopes. By contrast, amonoclonal antibody usually binds to a single epitope on the antigen surface. Cross-reactivity declines rapidly and nonlinearly with the num- ber of amino acid substitutions in the target epitope because a small number of amino acids control most of the binding energy. The seventh section discusses the specicity and cross-reactivity of Tcellresponses. The eighth section lists the ways in which hosts vary genetically in their responses to antigens. The germline genesthatcontribute to the T cellreceptor have some poly- morphisms that inuence recognition, but the germline B cell receptor genes do not carry any known polymorphisms. Each specic subset of an antigenic molecule recognized by an antibody or a T cell receptor denes an epitope. For example, insulin, a dimeric protein with 51 amino acids, has on its surface at least 115 antibody epitopes (Schroer et al. Nearly the entire surface of an antigen presents many overlapping domains that antibodies can discriminate as distinct epitopes (Benjamin et al. Epitopes have approximately 15 amino acids when dened by spatial contact of antibody and epitope during binding (Benjamin and Perdue 1996). Almost all naturally occurring antibody epitopes studied so far are composed of amino acids that are discontinuous in the primary se- quence but brought together in space by the folding of the protein.