Why are females at increased risk for common diseases that involve or target the immune system ?

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Differences in biological sex can dictate lifelong disease patterns, says a new study by Michigan State University researchers that links connections between specific hormones present before and after birth with immune response and lifelong immunological disease development.

Published in the most recent edition of the Proceedings of the National Academy of Sciences, the study answers questions about why females are at increased risk for common diseases that involve or target the immune system like asthma, allergies, migraines and irritable bowel syndrome.

The findings by Adam Moeser, Emily Mackey and Cynthia Jordan also open the door for new therapies and preventatives

“This research shows that it’s our perinatal hormones, not our adult sex hormones, that have a greater influence on our risk of developing mast cell-associated disorders throughout the lifespan,” says Moeser, Matilda R. Wilson Endowed Chair, professor in the Department of Large Animal Clinical Sciences and the study’s principle investigator.

“A better understanding of how perinatal sex hormones shape lifelong mast cell activity could lead to sex-specific preventatives and therapies for mast cell-associated diseases.”

Mast cells are white blood cells that play beneficial roles in the body.

They orchestrate the first line of defense against infections and toxin exposure and play an important role in wound healing, according to the study, “Perinatal Androgens Organize Sex Differences in Mast Cells and Attenuate Anaphylaxis Severity into Adulthood.”

However, when mast cells become overreactive, they can initiate chronic inflammatory diseases and, in certain cases, death. Moeser’s prior research linked psychological stress to a specific mast cell receptor and overreactive immune responses.

Moeser also previously discovered sex differences in mast cells. Female mast cells store and release more inflammatory substances like proteases, histamine and serotonin, compared with males.

Thus, female mast cells are more likely than male mast cells to kick-start aggressive immune responses. While this may offer females the upper hand in surviving infections, it also can put females at higher risk for inflammatory and autoimmune diseases.

“IBS is an example of this,” says Mackey, whose doctoral research is part of this new publication.

“While approximately 25% of the U.S. population is affected by IBS, women are up to four times more likely to develop this disease than men.”

Moeser, Mackey and Jordan’s latest research explains why these sex-biased disease patterns are observed in both adults and prepubertal children.

They found that lower levels of serum histamine and less-severe anaphylactic responses occur in males because of their naturally higher levels of perinatal androgens, which are specific sex hormones present shortly before and after birth.

“Mast cells are created from stem cells in our bone marrow,” Moeser said.

“High levels of perinatal androgens program the mast cell stem cells to house and release lower levels of inflammatory substances, resulting in a significantly reduced severity of anaphylactic responses in male newborns and adults.”

“We then confirmed that the androgens played a role by studying males who lack functional androgen receptors,” says Jordan, professor of Neuroscience and an expert in the biology of sex differences.

While high perinatal androgen levels are specific to males, the researchers found that while in utero, females exposed to male levels of perinatal androgens develop mast cells that behave more like those of males.

“For these females, exposure to the perinatal androgens reduced their histamine levels and they also exhibited less-severe anaphylactic responses as adults,” says Mackey, who is currently a veterinary medical student at North Carolina State University.

In addition to paving the way for improved and potentially novel therapies for sex-biased immunological and other diseases, future research based will help researchers understand how physiological and environmental factors that occur early in life can shape lifetime disease risk, particularly mast cell-mediated disease patterns.

“While biological sex and adult sex hormones are known to have a major influence on immunological diseases between the sexes, we’re learning that the hormones that we are exposed to in utero may play a larger role in determining sex differences in mast cell-associated disease risk, both as adults and as children,” Moeser said.


Over the last few years, there has been an unusual increase in atopic diseases, including allergies, asthma, eczema, rhinitis, and food sensitivities. In addition, there have been numerous cases of patients presenting with symptoms consistent with allergies, and/or inflammation, affecting many organs, but no recognizable trigger or too many non-allergic triggers.

These symptoms (Table 1) originate from mediators secreted (released) from mast cells and include flushing, pruritus, hypotension, gastrointestinal complaints, headaches, irritability, malaise, memory loss, and neuropsychiatric issues. As a result, a number of different names have been proposed to capture these symptoms such as mast cell diseases or mast cell disorders (MCD) and mast cell activation diseases or mast cell activation disorders (MCAD).

Table 1.

Common Symptoms in Patients With Mast Cell Mediator Disorders

• Cardiovascular: chest pain, hypotension, hypotensive syncope, tachycardia
• Dermatologic: angioedema, dermatographism, flushing, pruritus, urticaria pigmentosa
• Gastrointestinal: abdominal crumping/pain, bloating, diarrhea, esophagitis, nausea, vomiting
• Musculoskeletal: bone/muscle pain, degenerative disc disease, osteoporosis/osteopenia
• Naso-ocular: nasal congestion, pruritus, tearing
• Neurologic: headache, memory and concentration difficulties (brain fog), paresthesias, peripheral neuropathy
• Respiratory: hoarseness, sore throat, stridor, throat swelling, wheezing
• Systemic: anaphylaxis, fatigue

Unfortunately, these are many confusing aspects both in the naming and diagnosis of such disorders. First, the term ‘activation’ is typically reserved for activation of receptors or enzymes while ‘stimulation’ is used for cells. Second, stimulation of mast cells may imply proliferation without secretion of all or even any mast cell mediators as in the case of mast cell sarcoma.

Next, the term ‘secretion’ is usually reserved for mediators stored inside secretory granules, while the term ‘release’ is used for both pre-stored and newly synthesized mediators. Be it as it may, release of mast cell mediators can occur in many physiologic and pathologic settings.

To make matters worse, there are a number of other diseases that mimic and/or are comorbid with diseases involving mast cells (Table 2).

As a result, affected patients often go for 10–20 years and as many physicians of different specialties before a diagnosis is made, by which time they have been prescribed numerous medications, often with severe drug interactions that further complicate their presentation and course of their disease.

Table 2.

Conditions Often Comorbid With Mast Cell Diseases

• Chronic inflammatory response syndrome (CIRS)
• Fibromyalgia syndrome (FMS)
• Ehlers-Danlos Syndrome (EDS)
• Gulf War Illness (GWI)
• Interstitial cystitis/bladder pain syndrome (IC/BPS)
• Irritable bowel syndrome (IBS)
• Kounis syndrome
• Multiple chemical sensitivity syndrome (MCSS)
• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
• Post-Lyme syndrome
• Postural orthostatic tachycardia syndrome (POTS)
• Post-traumatic stress disorder (PTSD)

Mast cell biology
Mast cells are immune cells derived from hematopoietic precursors and mature in tissue microenvironments [1]. Mast cells are critical for the development of allergic reactions [2], but also act as sensors of environmental and psychological stress [3,4]. Perivascular mast cells were shown to probe cutaneous blood vessels by extending philopodia through endothelial gaps and capture immunoglobulin E (IgE) from blood vessels [4], a process that might also allow mast cells to sense and capture other circulating molecules. Mast cells also participate in the innate immune system (host defense against infectious pathogens, neutralization of toxins) and in the adaptive immune response [5–9], but also in antigen presentation [10,11] regulation of T cell responses [12–14], even in the absence of antigen presentation [15], autoimmunity [16], and inflammation [17–19].

Mast cells are located in tissues that interface with the external environment [20] and are stimulated primarily by IgE-dependent reactions (allergen). In addition to allergens, mast cells are also stimulated by a variety of different triggers (Table 3) that include bacteria, drugs, foods, fungi, heavy metals, organophosphates, viruses, and ‘danger signals’ [2], as well as certain neuropeptides including corticotropin-releasing hormone (CRH) [21], neurotensin (NT) [22,23], and substance P (SP). Both NT [24,25] and SP [26–29] are known to participate in inflammatory processes. Many cationic drugs have now been shown to stimulate mast cells through activation of the low affinity G-protein-coupled receptor MRGPRX2 [30]. Mast cells commonly respond to non-allergic triggers leading to mediators may also be released selectively without degranulation making it difficult to identify these mast cells with routine histology [31] (Table 4).

Table 3.

Cell Triggers of Mast Cell Degranulation

Acetylcholine
Complement fragments
– C3α, C4α, C5α
Drugs
– Local anesthetics
– Lactam antibiotics
– Neuromuscular junction blockers
– Vancomycin
IgE
IgG1
IgG4
Lysophosphatidylserine
Peptides
 - Adrenomedullin
 - CGRP
 - Endorphin
 - Endothelin
 - Eosinophil granule proteins
 - Hemokinin-1
 - Leptin
 - Mastoparan
 - Neurotensin
 - NGF
 - PTH
 - Somatostatin
 - SP
 - Thrombin
 - VIP
Physical conditions
 - Cold
 - Heat
 - Pressure
 - Stress
 - Vibration

Table 4.

Triggers of Mast Cells Without Degranulation

TriggersMediator
 Peptides
 CRHVEGF
 SCFIL-6
Cytokines
 IL-1βIL-6
 IL-33IL-31
 IL-33CX CL8 (IL-8)
 IL-33 + SPTNF, VEGF
Heavy metals
 Aluminum
 Cadmium
 Mercury
Herbicides
 Atrazine
 Glyphosate
Pathogens
 Borrelia (Lyme disease)*TNF
 LPSTNF
 Poly (I:C) (viruses)IL-6, TNF
 Sporothrix (mold)*IL-6, TNF

*Mycotoxins

Upon stimulation, mast cells secrete preformed mediators (Table 5) such as β-hexosaminidase (β-hex), histamine, tumor necrosis factor (TNF), and tryptase through rapid (1–5 min) degranulation. Mast cells are the only cell type that stores preformed TNF [32], which is rapidly secreted and influences T cell recruitment and activation [33–35].

Mast cells also release newly synthesized phospholipid products such as prostaglandin D2 (PGD2) and leukotrienes [36–38]. Mast cells also secrete numerous de novo synthesized protein mediators typically 6–24 h after stimulation such as cytokines [39], chemokines (TNF, CCL2, CCL8), and peptides hemokinin-1 (HK-1), and renin [19,40] (Table 4). Mast cell-derived CCL2 and CXCL8 enhance recruitment of other immune cells to the site of inflammation [41].

Table 5.

Mast Cell Mediators

Prestored
Biogenic Amines
 Dopamine
 Histamine
 5-Hydroxytryptamine (5-HT, serotonin)
Polyamines
 Spermidine, spermine
Cytokines
 TNF
Enzymes
 Arylsulfatases A
 Beta-hexosaminidase
 Beta-glucuronidase
 Beta-glucosaminidase
 Beta-D-galactosidase
 Carboxypeptidase A
 Cathepsins B,C, D, E, L
 Chymase
 Garnzyme B
 Kinogenases
 Phospholipases
 Renin
 Tryptase
  Metalloproteinases
 (CPA3, MMP9, ADAMTSS)
Growth factors
 FGF
 NGF
 SC
 TGFβ
 VEGF
Peptides
 ACTH
 Angiogenin
 Angiopoietin
 Calcitonin gene-related peptide
 Corticotropin-releasing hormone
 Endorphins
 Endothelin
 Hemokinin-1
 Kinins (bradykinin)
 Leptin
 Melatonin
 Neurotensin
RANKL
 Somatostatin
 Substance P
 Urocortin
 Vasoactive intestinal peptide
Proteoglycans
 Chondroitin sulfate
 Heparan sulfate
 Heparin
 Hyaluronic acid
 Serglin
De novo synthesized
Chemokines
 IL-8 (CXCL8), MCP-1 (CCL2), MCP-3 (CCL7),
 MCP-4, RANTES (CCL5), Eotaxin (CCL11)
Cytokines
 IL-1β, IL-4, IL-5, IL-6, IL-15, IL-17, IL-31, IL-33, TNF
Growth Factors
 SCF, β-FGF, neurotrophin 3, NGF,
 PDGF, TGFβ, VEGF
Nitric oxide
Phospholipid metabolites
 Leukotriene B4
 Leukotriene C4
 Platelet activating factor
 Prostaglandin D2

Moreover, corticotropin-releasing hormone (CRH or factor, CRF) is also synthesized by mast cells [42] implying that it could have autocrine effects [17,43]. In particular, CRHR-1 is expressed on human cultured mast cells, activation of which induces production of vascular endothelial growth factor (VEGF) without tryptase [21].

Mast cells can secrete IL-31, which is particularly pruritogenic [44], as well as additional ‘danger’ signals [45] (Table 4). Mitochondrial DNA (mtDNA) [34,46] can lead to auto-inflammatory responses [47–50], augment allergic responses [51], and has direct neurotoxic effects [52]. We had reported that mtDNA is increased in the serum of children with autism spectrum disorder (ASD) [53]. Another key danger signal is the alarmin IL-33 [54], which is secreted by fibroblasts and endothelial cells, and has been implicated in many allergic [55] and inflammatory [56] diseases. IL-33 augments the effect of IgE on secretion of histamine from mast cells and basophils [54,57]. It is interesting that the most widely used herbicide glyphosate induces IL-33 expression and airway inflammation [58].

We showed that IL-33 augments the ability of SP to stimulate secretion of VEGF from human mast cells without degranulation [59]. We recently also reported that SP and IL-33, when administered in combination, lead to an impressive increase in the gene expression and secretion of TNF [60] and IL-1β [61] from cultured human mast cells. Mast cells can secrete IL-33 [62,63], as well as the SP-related peptide HK-1 [64], implying autocrine augmentation.

Moreover, tryptase secreted from mast cells acts on extracellular IL-33 and generates mature, more active IL-33 [65], which then stimulates mast cells to secrete IL-1β, which in turn stimulates mast cells to secrete IL-6 [66]. In addition, mast cell-derived TGFβ promotes the development of Th17 cells and mast cells can also secrete IL-17 themselves [67].

Stimulated mast cells can secrete their numerous bioactive mediators [19,68,69] utilizing different signaling [70–73] and secretory [70,74] pathways. One important pathway is that of mammalian target of rapamycin (mTOR) [75], which we have shown to be stimulated by SP in human cultured mast cells [76]. The ability to secrete multiple mediators allows mast cells to actively interact with other cell types in their surrounding environment, especially T cells [77,78]. It is interesting that secretion of mast cell mediators have been shown to be regulated by a circadian clock [79,80].

Each mediator could lead to specific clinical features. For instance, histamine is associated with headaches, hypotension, and pruritus; tryptase with inflammation and fibrinogen lysis; cytokines and chemokines with constitutional symptoms of generalized inflammation and fatigue, PGD2 with flushing, and leukotrienes with bronchoconstriction.

As a result, mast cell-derived mediators could contribute to the pathogenesis of not only allergic diseases, asthma and mastocytosis [2], but also in atopic dermatitis, psoriasis, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [81], fibromyalgia syndrome (FMS) [82], coronary artery disease, and obesity [83], as well as ASD [17,50,84].

The severity of symptoms depends on many factors, such as the capacity of mast cells to secrete mediators, the levels of circulating IgE, the presence of cytokines and chemokines [85], especially IL-33 [59], as well as the co-existence of high-risk conditions, such as stimulation by hymenoptera venom(s) especially in patients suffering from mastocytosis [86–89].

Reactivity to wasp stings could lead to anaphylaxis, characterized by the sudden onset of severe flushing, swelling of the throat, bronchoconstriction, and hypotension that may progress to death [90].

Basophils also participate in allergic and other inflammatory reactions in-ways somewhat similar to that of mast cells, except that their main trigger is IgE and they do not contain tryptase [91,92]. Various assays have been proposed to document the involvement of basophil activation [93,94], via identification of CD63 and CD203c [93–95].

Classification and diagnostic features of mast cell disorders

This topic is quite confusing because of the use of different terminology by various specialists and consensus groups. For instance, the terms ‘mast cell diseases,’ ‘mast cell disorders,’ and ‘mast cell syndromes’ are often used interchangeably. In this review, the term ‘mast cell disorders’ is used as it includes many variants or subtypes.

Disorders involving mast cells [96,97] have been traditionally classified into three general categories: primary, secondary, and idiopathic [98,99]. However, new information on the genetic and epigenetic causes of the occurrence and severity of the symptoms [100] requires a new approach to the understanding and classification of these disorders as shown in Table 6.

Historically, ‘primary’ has been used to imply that these disorders are caused by genetic and/or epigenetic alterations leading to functional consequences in proliferation of mast cells in the bone marrow, skin, or other tissues/organs.

Table 6.

Classification of Mast Cell Disorders

Clonal Mast Cell Proliferation Disorders
1. Systemic mastocytosis (indolent, aggressive)
2. Cutaneous mastocytosis (urticarial pigmentosa, diffuse, telangiectasia macularis eruptive persistans)
3. Mast cell leukemia (MCL)
4. Mast cell sarcoma (MCS)
5. Extracutaneous mastocytoma (benign)
6. Monoclonal mast cell activation syndrome (MMAS)
Mast Cell Mediator Disorders (Idiopathic)
1. Monoclonal without abnormal clustering
2. Non-clonal
3. Idiopathic anaphylaxis (IA)
Reactive Mast Cell Proliferation/Mediator Release Disorders
1. IgE-mediated hypersensitivity reactions (e.g. food, insect anaphylaxis)
2. Drug-induced (e.g. vancomycin, opioids, taxanes, muscle relaxants, adenosine, nonsteroidal anti-inflammatory)
3. Mast cell hyperplasia (related with chronic infections, neoplasia, autoimmune conditions due to a possible excess of stem cell factor)

Activation threshold

There can be many reasons why mast cells can be stimulated to release their mediators (Table 8). Combination of triggers is more important than individual ones as they can lower the stimulation threshold of mast cells and ‘prime’ them for additional triggers [176] (Table 8).

There are numerous examples of synergistic effects of different triggers. We reported that combination of CRH and NT have synergistic action in stimulating VEGF secretion without tryptase [23], as well as induce the expression of each other’s receptors on human cultured mast cells [177].

We also showed that NT [177] and SP [178] increase expression of CRHR-1 on human mast cells. Moreover, SP increases expression of the IL-33 receptor ST2 and IL-33 increases NK-1 receptor on human mast cells [60]. Stimulation of mast cells by SCF also cross-activates ST2 [179].

Table 8.

Proposed Pathogenetic Mechanisms for Mast Cell Mediator Disorders

Lower activation threshold due to decreased expression/function of inhibitory molecules/pathways.
Intracellular
PTEN ↓
Chondroitin sulfate ↓
Sergylin ↓
Spermine/spermidine ↓
TGF beta ↓
Extracellular
Deflisinc ↓
IL-10 ↓
IL-37 ↓
IL-38 ↓
TGF beta ↓
Combination of non-allergic triggers
Peptides and Cytokines
SP + IL-33
NT + CRH
HK-1 + IL-33
Unappreciated triggers
CRH
Borrelia toxin
Bradykinin
CGRP
RCAP
Mycotoxins
NGF
Poly (lic)
PTH
Stress
Autocrine effects
Secretion of autocrine mediators
CRH
NK-1
Neurotensin
Tryptase
Autocrine receptor expression
Secretion of autocrine mediators
NT → CRHR-1 ↑
SP → CRHR-1 ↑
CRH → NTR ↑
SP → STZ ↑
IL-33 → NK-1 ↑

Comorbidities

Symptoms alone and response or lack thereof to medication is not sufficient for diagnosis as many of the symptoms could derive from other pathologic entities, whether they implicate mast cells or not. Nevertheless, the presence of multisystemic manifestations of symptoms at the same time and in the absence of any other systemic disease is highly suspicious for the presence of some mast cell disorder.

Symptoms suggestive of mast cell disorders that could be due to other conditions include:

(a) ‘flushing’ is associated also with menopause, carcinoid syndrome, pheochromocytoma, medullary carcinoma of the thyroid gland, as well as ingestion of niacin;

(b) cardiovascular disturbances may be related to myocardial infarction, endocarditis, autonomic dysfunction (dysautonomia), and postural orthostatic tachycardia syndrome (POTS),

(c) gastrointestinal problems may implicate irritable bowel syndrome (IBS), food toxicity especially from spoiled scombroid fish (e.g. tuna) that generates large amounts of histamine, or neuroendocrine tumors such as VIPoma;

(d) neurologic symptoms may be associated with panic attacks, migraines, epilepsy, and central nervous system (CNS) tumors;

(e) respiratory signs may be part of asthma, ‘heartburn,’ angioedema; and

(f) skin symptoms may be associated with acute toxic dermatoses, psoriasis, high parathyroid hormone (PTH), pemphigus vulgaris, and systemic lupus erythematosus (SLE).

Other comorbid diseases include coronary hypersensitivity [180,181], and multiple chemical sensitivity syndrome (Table 1) [182]. Two particularly relevant diseases are Myalgic Encephalomyelitits/Chronic Fatigue Syndrome (ME/CFS) and ASD [81], both of which have recently been associated with focal inflammation of the brain [183].

We had reported that children with mastocytosis have a 10-fold higher risk of developing ASD [184]. ASD is a pervasive neurodevelopmental disorder characterized by deficits in communication, as well as the presence of restricted, repetitive behaviors [185–187].

Allergic symptoms, due to mediators secreted from mast cells, have been significantly correlated with ASD severity [183,188]. A recent paper reported that diffuse cutaneous mastocytosis with the novel somatic KIT mutation K509I was associated with tuberous sclerosis, most of the may affected patient of which have ASD [189].

Large epidemiological studies have reported that allergies and asthma in preschoolers are significantly associated with ASD [190–193]. A similar conclusion was reached in a systematic review showing a significant association between atopic dermatitis and ASD [194]. Moreover, the presence of allergic symptoms strongly correlated with the presence of serum autoantibodies against brain peptides [195,196] in children with ASD [197].

Inflammation is a complicated immune process that involves numerous components depending on the tissue and trigger [198]. The specific role of cytokines in inflammation of the brain is still poorly understood as these ‘danger signals’ [45] are now divided into three different groups:

(a) inflammatory cytokines,

(b) alarmins, and

(c) stressorins, with distinct patterns of secretion and biological properties [199].

Innate immunity of the brain involves primarily microglia [200], which communicate with mast cells [201,202]. Mast cell-derived mediators, such as histamine and tryptase, can activate microglia [203] leading to secretion of pro-inflammatory mediators including interleukins IL-1β, IL-6, and TNF, known to be increased in the brain of children with ASD [204]. Mast cells are found in the brain [205], especially the hypothalamus, thalamus, and third ventricle [206,207]. Mast cells are also found in the pineal, the pituitary, and the thyroid glands [3].

Mast cells can function as the ‘immune gate to the brain’ [208] as they can regulate permeability of the blood–brain barrier (BBB) [209–211] and are involved in neuroinflammation and brain disorders [76,212].

Therefore, a detailed medical history including type, duration and triggers of symptoms, careful and focused physical examination, and specific laboratory tests, is necessary for a proper clinical evaluation. Family history is of great importance because the prevalence of MCD is higher among relatives of MCD patients than would be expected by chance [213].

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003574/


More information: Emily Mackey et al, Perinatal androgens organize sex differences in mast cells and attenuate anaphylaxis severity into adulthood, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1915075117

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