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1426 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431

Fig. 1. Schematic diagram of major activation (continuous lines) and suppression (dotted lines) regulatory pathways of a child’s defensive response to microbial infections.

Response timesto infectionare rapid(minutesto 4 h), intermediate (around 2 d),or slow (3 d or more). The bottom bar indicates potential effects on pre-leukemia cells. HPA:

hypothalamic-pituitary-adrenal; NK: natural killer;and see main text for other abbreviations.

by infectious diseases [10], as occurs in Burkitt lymphoma, the

premise of this paper is that the promotion of PBC-ALL is an aber-

rant immunological response to pre-natal infections, andespecially

post-natal infections that have a peak occurrence at 10 months old

in an affluent country such as the U.K. [11]. Intracellular pathogens

such as viruses, which invoke a particularly rapid innate immune

response, are the cause of approximately 90% of acute febrile ill-nesses in infants and young children [12]. There is a risk—especially

in neonates—that serious infections (including common extracel-

lular bacteria e.g., S. pneumoniae and H. influenzae) may put the

adaptive immune system and B-cells under proliferative stress

(Fig. 1).

The infective heat shock and lymphoid tissue recovery hypoth-

esis (herein called the ‘infective lymphoid recovery hypothesis’)

presented here proposes that pre-leukemic cells may be promoted

to overt PBC-ALL by common infections, primarily in young chil-

dren, according to the following etiologic process:

(a) hygienic conditions in infancy inhibit early immune priming,

thus reducing the efficacy of the secondary immune response

to later infections [13,14],(b) infectiousfevers induce expressionof heat shock proteins (HSP)

and pro-inflammatory T helper 1 (Th1) cell cytokines, both of 

which are conducive to cell survival and a hypermutatable state

[15],

(c) cytokine activation of  the hypothalamic–pituitary–adrenal

axis, resulting in infection-related glucocorticoid release and

transient involution of the thymus and other lymphoid organs,

causesa decline in antitumorimmunosurveillance and the mat-

uration arrest of B-cells,

(d) recurrent infections lead to cumulatively degraded stress

responses and higher homeostatic cytokine levels as the

body tries to reconstitute the atrophied/maturation-stalled

lymphoid tissue, thereby stimulating the proliferation of pre-

malignant precursor B-cells, and

(e) later release of Th2 cytokines augments a secondary and adap-

tive immune response,puttingadditionalproliferative stress on

bone marrow hematogones (benign B-lymphocyte precursors)

and pre-leukemic cells, thereby advancing overt leukemia.

The infective lymphoid recovery hypothesis is based on a three-

part methodology(Fig.2), andan extensive review of the associatedliterature, that in: Section 1 reconciles seemingly contradictory

protective and promoting evidence concerning infectious expo-

sure, hereafter called the ‘infection paradox’; Section 2 ascertains

the etiologic factors associated with individuals with congenital

syndromes who are susceptible to developing childhood leukemia,

especially PBC-ALL; and Section 3 f urther explores the evidence

for an infectious heat shock response and other factors identi-

fied that promote pre-leukemic cells to overt PBC-ALL. Lastly, the

infective lymphoid recovery hypothesis is compared with other

published hypotheses, demonstrating the ability of the infective

Fig. 2. The three major elements of the infective lymphoid recovery hypothesis.

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R.B. Richardson / Leukemia Research 35 (2011) 1425–1431 1427

lymphoid recovery hypothesis to explain certain PBC-ALL charac-

teristics, such as peak incidence at 2–5 years of age.

1. Infection paradox

This section provides an explanation for the often contrary sci-

entific evidence on the involvement and timing of  infections in

PBC-ALL etiology. Epidemiological studies and hypotheses identify

a significant but low risk of childhood leukemia from in utero infec-tious exposure during pregnancy [7,16]. McKinney et al. [17] f ound

that, in British children, ALLwas stronglyassociatedwith post-natal

viral diseases (e.g., chicken pox, rubella, measles and influenza)

occurring within 6 months of birth, withthe latent period to malig-

nancy ranging from 2.5 years to 5.5 years. Children over the age of 9

diagnosed with lymphoid cancers were associated with 4 or more

episodes of illness (e.g., influenza). A later U.K. case control study

[18] f ound that children aged 2–5 years diagnosed with ALL had an

excess of clinically diagnosed (e.g., presence of fever) viral andbac-

terial infections in infancy, especially during the neonatal period

(less than 1 month old). Two or more infections caused ALL to be

diagnosed earlier than for a single episode.

The apparent importance of  infective mechanisms in the pro-

motion of  childhood ALL led Kinlen [19], Greaves [14], and

Schmiegelow et al. [20] to postulate the ‘population-mixing the-

ory’, the ‘delayed first exposure hypothesis’, and the ‘adrenal

hypothesis’, respectively; the latter is examined in the Discus-

sion. Kinlen’s population-mixing theory proposed that workers

moving to isolated communities expose immunologically naïve

infants to specific infections and a higher risk of ALL [19]. Greaves’

delayed first exposure (or ‘delayed infection’) hypothesis is based

on the necessity of  an infectious challenge for the newborn’s

naïve immune system to mature and counter childhood ALL [14].

Accordingly, infants who experience a delayed exposure to infec-

tious agents are at greater risk of an abnormal lymphoproliferative

response. Support for Greaves’ hypothesis comes from studies

asserting that formal daycare (as compared to home care) and

increasing birth order provide infants with a significant protec-

tive effect against ALL due to an early, elevated infectious exposure[7,21,22]. Yet, as discussed above, there is also seemingly contrary

evidencethat multipleor prolonged episodes of common infections

in infancy promote the transition to overt ALL later in childhood

[17,18]. The infective lymphoid recovery hypothesis addresses this

infection paradox by presuming that mild infections early in life

prime the immune adaptive response, whereas later recurrent

infections in childhood provide the conditions conducive for the

accumulation of  cooperating oncogenic mutations necessary for

the promotion of PBC-ALL [5].

2. Etiologic factors identified fromcongenital syndromes

andother conditions

Congenital syndromes and other conditions (e.g., irradiation)

that are associated with an excess risk of  childhood leukemia

were examined in order to identify the etiologic factors that

increase vulnerabilityto acute myeloid leukemia (AML), andpartic-

ularly to PBC-ALL. Table 1 lists the relationship between childhood

leukemia and the following conditions: Down Syndrome (DS);

primary immunodeficiency disorders (i.e., ataxia–telangiectasia

and DiGeorge syndrome); chromosome fragility disorders (i.e.,

Bloom syndrome and Fanconi anemia); and Shwachman–Diamond

syndrome and neurofibromatosis (the latter arising from a tumor-

suppressor gene mutation) [23]. The association of childhood ALL

with lymphoid organ changes was reviewed to determine if a pos-

itive association was linked to a congenital (primary) feature or to

atrophy acquired due to (secondary) infection. Breastfeeding was

also considered because of its role in partially negating the risk of 

childhood leukemia.

Ionizing radiation is the best-documented environmental risk

factor that is significantly linked to childhood leukemia. Even so,

past risk assessments of  leukemia and bone cancer induced by

radionuclide intakes have been hampered by assuming the dose

and risk to quiescent and active (hematopoietic and mesenchymal)stem cells is the same [24]. The epidemiological evidence is gen-

erally positive for both in utero and post-natal exposure causing

excessive instances of ALL and AML, with a weaker association as

age increases [6,25,26]. In addition, high-dose treatments admin-

istered before 1950 to reduce purportedly enlarged thymuses in

infants led to an elevated incidence of thyroid cancer and leukemia

[27]. Even for low radiation doses of the whole body, there is the

potential for ALL to be initiated by DNA double strand breaks in

utero and promoted post-natally, perhaps by a heat shock response

that furthers inflammation and inhibits apoptosis [28].

Infections can be a concern in the chromosome fragility dis-

orders Bloom syndrome and Fanconi anemia, although thymus

abnormalities for either disorder are not prominent in the litera-

ture. Leukemia develops in about 10–15% of both Bloom syndromeand Fanconianemia patients.German[29] reports a similar number

of  acute lymphocytic and myelogenous leukemia cases for Bloom

syndrome. There is little evidence of an ALL incidence peak at 2–5

years for either disorder. In Fanconi anemia patients, AML is the

dominant form of  leukemia (>90% of cases) and is related to the

premature senescence of hematopoietic stem cells and the occur-

rence of myelodysplastic syndrome (MDS) [30,31]. This suggests

that senescence of the hematopoietic stem cell pool may promote

AML, yet inhibit the promotion of ALL.

 Table1

Characteristics relevant to childhood leukemia are compared for various conditions and assessed as observed (√ 

) or not observed (no symbol) as a prominent feature in the

literature.

Conditions Prone to

infections

Abnormal (or absent)

thymus

Abnormal non-thymic

lymphoid tissue

Excessive ratesof ALL

with peak 2–5 y

Excessive rates of 

‘non-PBC ALL’

leukemia

Ataxia–telangiectasia [33,34]√  √ 

(Mostly absent)√ 

S, L√ 

T-ALL

Breastfeeding (absence of) [36–38]√  √ 

Smaller√  √ 

AML

Bloom syndrome [29]√  √ 

AML

Congenital heart defects [32]√  √ 

(Absent)

DiGeorge syndrome [35]√ 

Down syndrome [39–42,48]√  √  √ 

BM, S , L√  √ 

AML

Fanconi anemia [30]√  √ 

BM√ 

AML

Infections (in utero and in infancy)

[16–18,59,61]

√  √ BM, S , L

√  √ AML

Ionizing radiation [6,25,27]√ 

High dose only√ 

BM, S, high doseonly√  √ 

AML

Neurofibromatosis [23]√  √ 

AML, JMML, T-ALL

Shwachman–Diamond syndrome [49]√ 

BM√ 

AML

ALL: acute lymphoblastic leukemia, AML: acute myeloid leukemia, BM:bone marrow, JMML: juvenile myelomonocytic leukemia, L: lymph,S: spleen, and T-ALL: T-cell ALL.

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1428 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431

There are several athymic medical conditions, including con-

genital heart defects, which are present in about 1% of  babies at

birth. Within weeks the thymus is generally removed surgically to

repair the heart. Young adults with congenital heart defects have

a T-cell profile similar to elderly non-affected adults 50 years their

senior [32]. The majority (80%) of ataxia-telangiectasia individuals

also have no thymus; for the 20% with the organ, it resembles that

of  a fetus [33]. Hypoplasia of  lymphoid tissue and infections are

common in ataxia–telangiectasia patients, who are also prone to

developing non-hematologic and hematologic neoplasms, includ-

ing T-cell ALL and AML [34]. The immunological abnormalities of 

DiGeorge syndrome individuals and their susceptibility to recur-

rent infections may be attributed to congenital underdevelopment

of  the thymus or, rarely, to its complete absence. B-cell matura-

tionandthe adult-like production of immunologlobulin-containing

cells does not normally take place in neonates without DiGeorge

syndrome, but surprisingly does take place in neonates with the

syndromewho lackT-suppressor activity[35]. ChildhoodALL is not

prominent in these conditions, and therefore it appears that infec-

tions in children who lack a functional thymus are not conducive

to the development of ALL.

Breastfeeding (as compared to formula feeding) can double

thymic size by 4 months of  age, improve CD4+ and CD8+ T-

lymphocyte concentrations, and reduce the risk of respiratory tractinfections in infants by up to two-thirds [36,37]. A meta-analysis

of  14 case-control studies revealed that long-term breastfeeding

reduces the risk of childhood leukemia, particularly ALL; although

the results of individual studies are ambiguous probably due to

their small size [38]. These breastfeeding studies highlight the

importance of even modest changes in thymic size upon the post-

natal development of immunocompetence and ALL.

For most congenital syndromes susceptible to leukemia, there

is limited data on ALL subtypes and their relative risk; of these con-

ditions, DS children are the best studied. DS children are highly

vulnerable to respiratory tract infections and an increased occur-

rence of thymic aberrations [39]. Marked (T- and B-) lymphocyte

depletionhas also been observed in the spleenand lymph glandsof 

DS infants perhaps due to congenital factors [40]. It is well knownthat individuals with DS have a greatly elevated risk of childhood

leukemia: the relative risks are about 10–30 times higher than

controls [39,41,42]. Neonates with DS exhibit a range of hemato-

logic abnormalities, including transient leukemia and MDS, both

of  which can precede AML. For DS children, the frequency of ALL

is about one and a half times that of  AML, as compared to 4:1 for

non-DS children [42].

The vulnerability of DS children to immunological defects and

PBC-ALL may be affected by additional copies of genes on chro-

mosome 21, such as the oncogene  AML1, and genes of the HSP70

family and interferon (IFN) receptors [43]. Regarding the latter, DS

individuals exhibit increased levels of the Th1 pro-inflammatory

cytokine IFN- associated with stimulating the formation of com-

mon lymphoid progenitors [44,45]. IFN-inducible genes indicativeof  a viral infection are highly expressed in the hyperdiploid PBC-

ALL variant that constitutes a large part of the incidence peak [46].

Trisomy 21 is present in the bone marrow of all DS individuals, and

it may not be a coincidence that it is also present in half of non-DS

childhood ALL cases [47]. Therefore, trisomy 21 could be involved

in promoting ALL in DS and non-DS children, as both groups have

a similar trend in ALL age-specific incidence rates [48]. A differ-

ence is that the DS peak incidence is more pronounced and the

promotion/latent period possibly shorter than for non-DS.

In summary, a high risk of bone marrow dysfunction is present

in children with chromosome breakage syndromes (i.e. ataxia

-telangiectasia, Bloom syndrome and Fanconi anemia), DS and

Shwachman-Diamondsyndrome [49]. These congenital syndromes

display segmental symptoms of accelerated ageing, as does MDS,

a disease that can advance to AML, but not ALL. Similarly, thymec-

tomy in congenital heart defect patients and the impaired thymic

processes in ataxia–telangiectasia, DiGeorge syndrome and DS,

prematurely age the immune system and downgrade the abil-

ity to countermand infections and tumors [32]. Nevertheless,

the apparent lack of   excessive rates of  ALL in children with

ataxia–telangiectasia, congenital heart defects, and DiGeorge syn-

drome implies that the absence or removal of  an infant’s thymus

is not enough in itself  to induce PBC-ALL (Table 1). DS studies

indicate an abnormal infective Th1 signaling response to an IFN--dependentimmunosurveillance mechanism.Therefore, etiologic

factors conducive to the promotion of childhood ALL appear to be

recurrent infections, followed by thymic atrophy, lymphoid tissue

abnormalities, sustained proliferative signaling and reconstitution

of lymphoid tissue.

3. Infective heat shock response and lymphoid tissue

recovery

Natural stressors,such as heat stress, malnutritionand infection,

can invoke a heat shock response. Evidence is presented below to

demonstrate that recurrent infective and heat shock responses in

the fetus or infant are linked to defective differentiation of bloodcells, overproduction of immature B-lymphocytes, and inhibition

of B-cell death—genetic hallmarks of PBC-ALL [5]. HSPs generated

by the host upon invasion by viruses and bacteria (or the bacteria’s

own HSPs) rapidly activate the innate immune system. This is fol-

lowed by a hypothalamic–pituitary–adrenal response [50], as well

as acute involution of the thymus (alternatively called ‘transient

involution’) and of other lymphoid organs and tissues.

A mutation in the gatekeeper p53 gene—the most common

mechanism by which a neoplasm escapes apoptosis—is weakly

associatedwith leukemia.Only 5% of childhoodALL cases at diagno-

sis exhibit p53 mutations, which is among the lowest p53 mutation

incidence of all cancers [51]. HSPs may be a more prevalent means

of avoiding cell death in leukemia. An elevated expression of HSPs

has been detected in various forms of leukemia (e.g., high constitu-tiveexpressionof HSP90 is associated withthe proliferationof ALL

cells) [52]. Small heat shock protein HSP27 isoforms are associated

with common ALL in a uniquely characteristic manner, as HSP27

is synthesized during both normal and abnormal development of 

immature lymphoid cells at the pre-B-cell stage of  differentia-

tion [53]. There is a greater frequency of human leukocyte antigen

(HLA) haplotypes and HLA-complex-linked HSP70 genes in boys

as compared to girls [54]. This, and males’ greater susceptibility

to infections and stress, may possibly influence the incidence of 

childhood ALL being slightly higher in boys than in girls [55].

HSP60, HSP70, and HSP90 induce macrophages and other cells

to release Th1pro-inflammatory cytokines, including tumor necro-

sis factor- (TNF-), interleukin-2 (IL-2) and IL-12 [56]. About

two days after a heat shock response, Th1 cytokines stimulateincreased glucocorticoid secretion during the post-stress recov-

ery period, thereby causing transient involution of  the thymus

and limiting over-activity by the immune and inflammatory path-

ways. Chronic (particularly bacterial) infections and heat shock

result in cumulative stress-induced weakening of  the glucocorti-

coid receptor-mediated recovery response [57]. Thymic involution

and thymic lymphocyte depletion measured in fetuses and young

children have been shown to be related to the duration of pre-natal

and post-natal acute infections, respectively [58,59]. In addition,

limited atrophy in the spleen and lymph nodes was observed

in those who died after a period of  acute illness [58,60]. These

anatomical findings show that after sustained pre- or post-natal

infections, there is cumulative degradation of  lymphoid tissue

requiring reconstitution.

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Infants experiencing infections exhibit thymic involution and

can be expected to have lesser immunosurveillance by CD4+ and

CD8+ cells, similar to formula-fed infants [36]. In addition, the

lower thymic function affects the ability to complete the B-cell

maturation process and to generate high-affinity memory cells

and antibody formation [61]. Hematogones make up on average

one-third of  the bone marrow cells of  living pre-term neonates

[62]. Normally, marrow lymphocyte maturation is probably trig-

gered by birth, with ten times fewer hematogones at 2–5 years

old. Hematogones are especially prominent in children exhibiting

a serious complication(e.g.,acute thrombocytopenicpurpura)after

viral infections such as measles and chicken pox [63]. Congenital

cytomegalovirus (CMV) infections are associated with post-natal,

excessive hematogones of  immature benign cell types similar to

those characteristic of infant ALL (a distinct PBC-ALL group, most

with MLL gene rearrangements) that usually occurs in infants, 0–1

year old [64]. Further evidence of  arrested bone marrow matu-

ration is provided by post-uterine CMV infections preceding the

observation of hematogones of PBC-ALL-like cell types [65]. There-

fore, perinatal infections seem to be an opportunistic mechanism

for bone marrow to undergo maturation arrest and acquire the

immunophenotypic aberrancies characteristic of PBC-ALL.

Key components of any PBC-ALL etiological hypothesis are the

biological mechanisms that can stimulate excessive B-cell prolif-eration. A B-cell response is not limited to bacterial infections; for

instance, the influenza virus induces IFN-mediated B-cell activa-

tion and the production of  antiviral antibodies [66]. In addition,

respiratory syncytial virus—the principal etiologic agent of  res-

piratory infections in infants and young children—provokes both

a heat shock and Th2 response [67]. There is also evidence that

dysregulation of the transforming growth factor- (TGF-) path-

way, a Th2 cytokine produced in response to infection and that

accelerates thymic involution, is involved in the promotion of TEL-

 AML1-positive ALL [68].

Lastly, there is evidence of B-cell proliferative signaling by the

homeostatic agent IL-7, which is associated with infections and

reconstitutions of  maturation-stalled or atrophied lymphoid tis-

sues. IL-7 serum levels are elevated after infections in general, andaugment reconstitution of the thymus and spleen [69,70]. Perhaps

related to DS’s congenital vulnerabilityto childhood ALL,IL-7 levels

aresimilarly raised in DS individuals aged 4–25years oldwho have

no acquired diseases [71]. IL-7 not only stimulates the proliferation

of normal B- and T-cell precursors and T-lymphocytes, but it also

acts as a growth factor for PBC-ALL and T-cell ALL [72].

In summary, the seemingly contradictory aspects of  infection

and PBC-ALL risk have been explained; the etiological factors,

derived from conditions with varying susceptibility to childhood

leukemia, have been identified; and further evidence that supports

the infective lymphoid recovery hypothesis has been presented.

The hypothesis asserts that recurrent infection-driven heat shock

and lymphoid involution is followed by an IL-7-mediated immune

recovery that places increased proliferative pressure on immatureB-cells, which in turnpromotesthe transformationof pre-leukemic

cells into overt PBC-ALL.

4. Comparison of PBC-ALL etiological hypotheses

The adrenal hypothesis, as recently proposed by Schmiegelow

et al. [20], explains the lower risk of  common ALL experienced

by children exposed to early infections by citing changes in the

hypothalamic–pituitary–adrenal axis. This theory maintains that

infections raise glucocorticoid (e.g., cortisol) levels, which effec-

tively induce apoptosis of thymocytes, reduce proliferative stress,

and lead to the apoptosis of  pre-existing leukemic cells. Strong

evidence is given in support of  the adrenal hypothesis—namely,

that the administration of glucocorticoid (either on its own or as

part of an anti-inflammatory, immunosuppressive and chemother-

apeutic ALL agent) can produce a four-log reduction of malignant

lymphoblasts in children [73]. However, the adrenal hypothesis

does not address the fact that after infection-mediated atrophy

of  lymphoid tissue, there is reconstitution that puts proliferative

stress on apoptotic-resistant, pre-leukemic cells. Also, the adrenal

hypothesis only accounts for the first of  two seemingly contra-

dictory mechanisms of the infection paradox—that infections can

provide both a protective and promotional mechanism in PBC-ALL

etiology [14,17–19].

The infective lymphoid recovery hypothesis, however, is able

to reconcile both components of the infection paradox. It asserts

that protection from PBC-ALL is afforded by early, mild infections

that prime an adaptive immune response. Any delay in this prim-

ing (more likely to occur in hygienic, socially isolated, and affluent

societies) places greater reliance, when defending against infec-

tious pathogens, on heat shock activation of the innate immune

responseandon a pro-inflammatory state. However,laterrecurrent

exposure to infections—especially in infancy—has an accumula-

tiveeffect on activationof the hypothalamic–pituitary–adrenal axis

and transient involution of lymphoid tissues, which may enhance

the selection of a resistant, pre-leukemic strain. The subsequent

reconstitution of  lymphoid tissues places proliferating stress onhematogones and pre-leukemic cells.

Greaves [8] rightly states that any credible hypothesis on the

etiology of childhood ALL needs to explain why ALL incidence rates

in children increase by ∼1% per annum, and why the incidence

peak at 2–5 years is more prominent in affluent societies as com-

paredto populations withpoor socio-economic conditionsand high

child mortality rates [7,10,20,74]. One factor that should be con-

sidered is that in less-affluent or developing countries, families are

generally larger and live in closer quarters; this provides a par-

allel environment to the daycare centers in the developed world

that immunologically prime young children and protect against

childhood ALL [21,22]. Another factor likely influencing the low

ALL incidence rates in children of  developing countries is their

high rate of  breastfeeding [75], which furthers thymic enlarge-ment that improves the immunosurveillance of pre-leukemic cells

and lessens the need for lymphoid tissue reconstitution. On the

other hand, affluence and improvedhealthcare lead to moreinfants

surviving recurrent infectious episodes (especially important to

the more vulnerable, such as those with DS) [25] and living to

experience accumulated lymphoid tissue atrophy and recovery,

thereby putting greater proliferative stress on hematogones and

pre-leukemic cells. The infective lymphoid recovery hypothesis

predicts that this intense transformative pressure shortens the

promotion/latent period, concatenating the PBC-ALL diagnoses

towards late infancy (the period of maximum infection rates) [11]

and resulting in a steeper and more pronounced peak incidence.

The widely accepted hygiene hypothesis explains the elevated

incidence of allergies in developed countries based on lesser expo-sure to infections during early childhood [13]. It is compatible

with Greaves’ [14] hypothesis (as well as the infective lymphoid

recovery hypothesis), which contends that the risk of  childhood

ALL is reduced by exposure to priming infections in early life.

Notwithstanding, Schmiegelow and colleagues [76] conducted a

meta-analysis of 11 case–control studies and found an inverseasso-

ciation between ALL and atopic allergies in children (e.g., asthma,

eczema, and hay fever). Similarly, DS cases susceptible to ALL are

associated with a significant deficit of asthma [41]. Allergies involve

an excessive Th2 anti-inflammatory response and class-switching

to enhance the production of  IgE antibodies. A possible expla-

nation for the inverse relationship is that PBC-ALL is associated

more strongly with a heat shock mediated Th1 response and lym-

phoid tissue reconstitution, as compared to aTh2 response. Further

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1430 R.B. Richardson / Leukemia Research 35 (2011) 1425–1431

support for a Th1 response being linked to PBC-ALL is provided by

observations of  malnourished children without infections from a

developing country, which generally have low incidences of ALL

[50]. Although starvation is associated with a heat shock response

these childrendo not haveelevatedlevels of serumcortisolandTh1

pro-inflammatory cytokines.

5. Predictions and conclusion

The infective lymphoid recovery hypothesis generates testable

predictions. One is that the risk of   PBC-ALL will be generally

enhanced in those young children who experience recurrent infec-

tions and elevated levels of IL-7 indicating a lymphoid recovery.

Another prediction is that neonates and infants, compared to older

children, will exhibit a greater gain in the frequency of oncogenic

mutations due to infections [15]. Issues warranting further study

include determining if  the protective and promotional facets of 

the infection paradox apply differently to PBC-ALL immunologi-

cal (e.g., pro-B, pre-B) or cytogenetic variants, as suggested by high

virus-mediated INF- levels associated with the hyperdiploid sub-

type [46]. A better understanding of  PBC-ALL etiology would be

gained from collecting further statistical data on ALL subtypes for

congenital syndromes and other vulnerable conditions.In conclusion, a significant aspect of  the infective lymphoid

recovery hypothesis is that it appears to explain the infection para-

dox and the prominence of the ALL peak incidence as being due to

the shortening of the promotion/latent period by surviving multi-

ple infections andan over-expressive lymphoid-recovery response.

It is hoped thatthis hypothesis will encourage further research and

testing of the etiological process proposed, thereby leading to a

better understanding and treatment of common childhood ALL.

 Acknowledgements

The author thanks Mel Greaves of  The Institute of  Cancer

Research, London, U.K.; Johann Hitzler of The Hospital for Sick Chil-

dren Research Institute, University of Toronto, Canada; and PatriciaMcKinneyof Universityof Leeds,U.K.for their review of earlydrafts.

The author also thanks Elizabeth Bond for careful proofreading of 

this manuscript.

Funding source: None.

Contributions: Richard B. Richardson is the sole author and con-

tributor.

Conflict of  interest : Richard B. Richardson has no conflict to

declare.

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